RBCC

Full text data of KRAS

KRAS (KRAS2, RASK2) [Confidence: high (present in two of the MS resources)]
GTPase KRas (K-Ras 2; Ki-Ras; c-K-ras; c-Ki-ras; GTPase KRas, N-terminally processed; Flags: Precursor)

hRBCD IPI00423570
IPI00423570 Splice isoform 2B of P01116 Transforming protein p21 Splice isoform 2B of P01116 Transforming protein p21 membrane n/a 1 n/a n/a n/a n/a n/a n/a 3 n/a 5 4 3 3 3 1 2 n/a 1 1 cytoplasmic and membrane associated QGVDDAFYTLVR (only unique peptide existing, found at least 3 times) expected molecular weight found in band between 14-17 kDa

Comments
Isoform P01116-2 was detected.

UniProt P01116
ID RASK_HUMAN Reviewed; 189 AA.
AC P01116; A8K8Z5; B0LPF9; P01118; Q96D10;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=GTPase KRas;
DE AltName: Full=K-Ras 2;
DE AltName: Full=Ki-Ras;
DE AltName: Full=c-K-ras;
DE AltName: Full=c-Ki-ras;
DE Contains:
DE RecName: Full=GTPase KRas, N-terminally processed;
DE Flags: Precursor;
GN Name=KRAS; Synonyms=KRAS2, RASK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 2A AND 2B).
RX PubMed=6308466; DOI=10.1038/304501a0;
RA McGrath J.P., Capon D.J., Smith D.H., Chen E.Y., Seeburg P.H.,
RA Goeddel D.V., Levinson A.D.;
RT "Structure and organization of the human Ki-ras proto-oncogene and a
RT related processed pseudogene.";
RL Nature 304:501-506(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 2A AND 2B).
RC TISSUE=Lung carcinoma;
RX PubMed=6308465; DOI=10.1038/304497a0;
RA Shimizu K., Birnbaum D., Ruley M.A., Fasano O., Suard Y., Edlund L.,
RA Taparowsky E., Goldfarb M., Wigler M.;
RT "Structure of the Ki-ras gene of the human lung carcinoma cell line
RT Calu-1.";
RL Nature 304:497-500(1983).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 2A AND 2B).
RC TISSUE=Colon carcinoma, and Lung;
RX PubMed=6308467; DOI=10.1038/304507a0;
RA Capon D.J., Seeburg P.H., McGrath J.P., Hayflick J.S., Edman U.,
RA Levinson A.D., Goeddel D.V.;
RT "Activation of Ki-ras2 gene in human colon and lung carcinomas by two
RT different point mutations.";
RL Nature 304:507-513(1983).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 2A AND 2B), AND VARIANT
RP COLON CANCER VAL-12.
RC TISSUE=Colon carcinoma;
RX PubMed=6092920;
RA McCoy M.S., Bargmann C.I., Weinberg R.A.;
RT "Human colon carcinoma Ki-ras2 oncogene and its corresponding proto-
RT oncogene.";
RL Mol. Cell. Biol. 4:1577-1582(1984).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2B).
RX PubMed=3310850;
RA Kahn S., Yamamoto F., Almoguera C., Winter E., Forrester K.,
RA Jordano J., Perucho M.;
RT "The c-K-ras gene and human cancer (review).";
RL Anticancer Res. 7:639-652(1987).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2B).
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2B), AND VARIANT LUNG
RP CARCINOMA HIS-61.
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2B).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2B), AND VARIANT LUNG
RP CARCINOMA HIS-61.
RC TISSUE=Lung carcinoma;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-37, AND VARIANT LUNG CARCINOMA
RP CYS-12.
RC TISSUE=Lung carcinoma;
RX PubMed=6320174; DOI=10.1073/pnas.81.1.71;
RA Nakano H., Yamamoto F., Neville C., Evans D., Mizuno T., Perucho M.;
RT "Isolation of transforming sequences of two human lung carcinomas:
RT structural and functional analysis of the activated c-K-ras
RT oncogenes.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:71-75(1984).
RN [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-96.
RC TISSUE=Pancreatic carcinoma;
RX PubMed=3855240; DOI=10.1016/S0006-291X(85)80140-6;
RA Hirai H., Okabe T., Anraku Y., Fujisawa M., Urabe A., Takaku F.;
RT "Activation of the c-K-ras oncogene in a human pancreas carcinoma.";
RL Biochem. Biophys. Res. Commun. 127:168-174(1985).
RN [14]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-37, AND VARIANT GASC VAL-12.
RX PubMed=3034404;
RA Deng G., Lu Y., Chen S., Miao J., Lu G., Li H., Cai H., Xu X.,
RA Zheng E., Liu P.;
RT "Activated c-Ha-ras oncogene with a guanine to thymine transversion at
RT the twelfth codon in a human stomach cancer cell line.";
RL Cancer Res. 47:3195-3198(1987).
RN [15]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-36, AND VARIANT BLADDER/LUNG
RP CANCER ARG-12.
RC TISSUE=Lung carcinoma;
RX PubMed=6695174; DOI=10.1126/science.6695174;
RA Santos E., Martin-Zanca D., Reddy P.E., Pierotti M.A., Porta G.,
RA Barbacid M.;
RT "Malignant activation of a K-ras oncogene in lung carcinoma but not in
RT normal tissue of the same patient.";
RL Science 223:661-664(1984).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-37.
RX PubMed=3932274;
RA Sekiya T., Tokunaga A., Fushimi M.;
RT "Essential region for transforming activity of human c-Ha-ras-1.";
RL Jpn. J. Cancer Res. 76:787-791(1985).
RN [17]
RP PROTEIN SEQUENCE OF 1-41; 43-147 AND 150-161, CLEAVAGE OF INITIATOR
RP METHIONINE, ACETYLATION AT MET-1 AND THR-2, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RA Bienvenut W.V., Calvo F., Kolch W.;
RL Submitted (FEB-2008) to UniProtKB.
RN [18]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 38-96.
RC TISSUE=Lung carcinoma;
RX PubMed=6096811; DOI=10.1093/nar/12.23.8873;
RA Yamamoto F., Perucho M.;
RT "Activation of a human c-K-ras oncogene.";
RL Nucleic Acids Res. 12:8873-8885(1984).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP ACETYLATION AT LYS-104, AND VARIANT VAL-12.
RX PubMed=22711838; DOI=10.1073/pnas.1201487109;
RA Yang M.H., Nickerson S., Kim E.T., Liot C., Laurent G., Spang R.,
RA Philips M.R., Shan Y., Shaw D.E., Bar-Sagi D., Haigis M.C.,
RA Haigis K.M.;
RT "Regulation of RAS oncogenicity by acetylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:10843-10848(2012).
RN [21]
RP VARIANT BREAST CANCER ASP-13.
RX PubMed=3627975; DOI=10.1093/nar/15.15.5963;
RA Kozma S.C., Bogaard M.E., Buser K., Saurer S.M., Bos J.L., Groner B.,
RA Hynes N.E.;
RT "The human c-Kirsten ras gene is activated by a novel mutation in
RT codon 13 in the breast carcinoma cell line MDA-MB231.";
RL Nucleic Acids Res. 15:5963-5971(1987).
RN [22]
RP VARIANT BLADDER CANCER THR-59.
RX PubMed=1553789; DOI=10.1007/BF00296523;
RA Grimmond S.M., Raghavan D., Russell P.J.;
RT "Detection of a rare point mutation in Ki-ras of a human bladder
RT cancer xenograft by polymerase chain reaction and direct sequencing.";
RL Urol. Res. 20:121-126(1992).
RN [23]
RP VARIANTS PANCREATIC CARCINOMA ASP-12 AND VAL-12.
RX PubMed=8439212;
RA Motojima K., Urano T., Nagata Y., Shiku H., Tsurifune T.,
RA Kanematsu T.;
RT "Detection of point mutations in the Kirsten-ras oncogene provides
RT evidence for the multicentricity of pancreatic carcinoma.";
RL Ann. Surg. 217:138-143(1993).
RN [24]
RP VARIANTS GASC SER-12 AND ASP-12.
RX PubMed=7773929;
RX DOI=10.1002/1097-0142(19950615)75:12<2794::AID-CNCR2820751203>3.0.CO;2-F;
RA Lee K.H., Lee J.S., Suh C., Kim S.W., Kim S.B., Lee J.H., Lee M.S.,
RA Park M.Y., Sun H.S., Kim S.H.;
RT "Clinicopathologic significance of the K-ras gene codon 12 point
RT mutation in stomach cancer. An analysis of 140 cases.";
RL Cancer 75:2794-2801(1995).
RN [25]
RP INVOLVEMENT IN AML, VARIANT GLY-10 INS, AND CHARACTERIZATION OF
RP VARIANT GLY-10 INS.
RX PubMed=8955068; DOI=10.1074/jbc.271.51.32491;
RA Bollag G., Adler F., elMasry N., McCabe P.C., Conner E. Jr.,
RA Thompson P., McCormick F., Shannon K.;
RT "Biochemical characterization of a novel KRAS insertion mutation from
RT a human leukemia.";
RL J. Biol. Chem. 271:32491-32494(1996).
RN [26]
RP VARIANTS GASC ASN-5; VAL-12; ASP-13 AND THR-59.
RX PubMed=14534542; DOI=10.1038/sj.onc.1206749;
RA Lee S.H., Lee J.W., Soung Y.H., Kim H.S., Park W.S., Kim S.Y.,
RA Lee J.H., Park J.Y., Cho Y.G., Kim C.J., Nam S.W., Kim S.H., Lee J.Y.,
RA Yoo N.J.;
RT "BRAF and KRAS mutations in stomach cancer.";
RL Oncogene 22:6942-6945(2003).
RN [27]
RP VARIANT PYLOCYTIC ASTROCYTOMA ARG-13.
RX PubMed=16247081; DOI=10.1212/01.wnl.0000180409.78098.d7;
RA Sharma M.K., Zehnbauer B.A., Watson M.A., Gutmann D.H.;
RT "RAS pathway activation and an oncogenic RAS mutation in sporadic
RT pilocytic astrocytoma.";
RL Neurology 65:1335-1336(2005).
RN [28]
RP VARIANTS NS3 GLY-152 (ISOSORM 2) AND VAL-153 (ISOFORM 2).
RX PubMed=16773572; DOI=10.1086/504394;
RA Carta C., Pantaleoni F., Bocchinfuso G., Stella L., Vasta I.,
RA Sarkozy A., Digilio C., Palleschi A., Pizzuti A., Grammatico P.,
RA Zampino G., Dallapiccola B., Gelb B.D., Tartaglia M.;
RT "Germline missense mutations affecting KRAS Isoform B are associated
RT with a severe Noonan syndrome phenotype.";
RL Am. J. Hum. Genet. 79:129-135(2006).
RN [29]
RP VARIANTS LUNG CARCINOMA CYS-12; ASP-12; SER-12; VAL-12 AND HIS-61.
RX PubMed=16533793; DOI=10.1158/1078-0432.CCR-05-1981;
RA Tam I.Y.S., Chung L.P., Suen W.S., Wang E., Wong M.C.M., Ho K.K.,
RA Lam W.K., Chiu S.W., Girard L., Minna J.D., Gazdar A.F., Wong M.P.;
RT "Distinct epidermal growth factor receptor and KRAS mutation patterns
RT in non-small cell lung cancer patients with different tobacco exposure
RT and clinicopathologic features.";
RL Clin. Cancer Res. 12:1647-1653(2006).
RN [30]
RP VARIANT CFC2 ARG-60.
RX PubMed=16474404; DOI=10.1038/ng1749;
RA Niihori T., Aoki Y., Narumi Y., Neri G., Cave H., Verloes A.,
RA Okamoto N., Hennekam R.C.M., Gillessen-Kaesbach G., Wieczorek D.,
RA Kavamura M.I., Kurosawa K., Ohashi H., Wilson L., Heron D.,
RA Bonneau D., Corona G., Kaname T., Naritomi K., Baumann C.,
RA Matsumoto N., Kato K., Kure S., Matsubara Y.;
RT "Germline KRAS and BRAF mutations in cardio-facio-cutaneous
RT syndrome.";
RL Nat. Genet. 38:294-296(2006).
RN [31]
RP VARIANTS NS3 ILE-14 AND ILE-58, VARIANT CFC2 ARG-34, AND
RP CHARACTERIZATION OF VARIANTS NS3 ILE-14 AND ILE-58.
RX PubMed=16474405; DOI=10.1038/ng1748;
RA Schubbert S., Zenker M., Rowe S.L., Boell S., Klein C., Bollag G.,
RA van der Burgt I., Musante L., Kalscheuer V., Wehner L.-E., Nguyen H.,
RA West B., Zhang K.Y.J., Sistermans E., Rauch A., Niemeyer C.M.,
RA Shannon K., Kratz C.P.;
RT "Germline KRAS mutations cause Noonan syndrome.";
RL Nat. Genet. 38:331-336(2006).
RN [32]
RP VARIANTS [LARGE SCALE ANALYSIS] ALA-12; ASP-12; SER-12; VAL-12;
RP ASP-13; ARG-61; ASN-117 AND THR-146.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [33]
RP VARIANT NS3 GLU-5.
RX PubMed=17468812; DOI=10.1007/s10038-007-0146-1;
RA Bertola D.R., Pereira A.C., Brasil A.S., Albano L.M., Kim C.A.,
RA Krieger J.E.;
RT "Further evidence of genetic heterogeneity in Costello syndrome:
RT involvement of the KRAS gene.";
RL J. Hum. Genet. 52:521-526(2007).
RN [34]
RP VARIANTS NS3 ILE-14; ARG-22; LEU-34; GLN-34; MET-36 AND VAL-153
RP (ISOFORM 2), VARIANT CFC2 GLU-22, VARIANT NS3/CFC2 ILE-156 (ISOFORM
RP 2), AND VARIANTS ASN-5 AND LEU-156 (ISOFORM 2).
RX PubMed=17056636; DOI=10.1136/jmg.2006.046300;
RA Zenker M., Lehmann K., Schulz A.L., Barth H., Hansmann D., Koenig R.,
RA Korinthenberg R., Kreiss-Nachtsheim M., Meinecke P., Morlot S.,
RA Mundlos S., Quante A.S., Raskin S., Schnabel D., Wehner L.E.,
RA Kratz C.P., Horn D., Kutsche K.;
RT "Expansion of the genotypic and phenotypic spectrum in patients with
RT KRAS germline mutations.";
RL J. Med. Genet. 44:131-135(2007).
RN [35]
RP VARIANTS NS3 ILE-58 AND SER-60.
RX PubMed=19396835; DOI=10.1002/ajmg.a.32786;
RA Kratz C.P., Zampino G., Kriek M., Kant S.G., Leoni C., Pantaleoni F.,
RA Oudesluys-Murphy A.M., Di Rocco C., Kloska S.P., Tartaglia M.,
RA Zenker M.;
RT "Craniosynostosis in patients with Noonan syndrome caused by germline
RT KRAS mutations.";
RL Am. J. Med. Genet. A 149:1036-1040(2009).
RN [36]
RP CHARACTERIZATION OF VARIANTS NS3 ILE-14; ARG-22; LEU-34; ILE-58 AND
RP VAL-153 (ISOFORM 2), CHARACTERIZATION OF VARIANTS CFC2 GLU-22; ARG-34
RP AND ARG-60, AND CHARACTERIZATION OF VARIANTS ASN-5 AND LEU-156
RP (ISOFORM 2).
RX PubMed=20949621; DOI=10.1002/humu.21377;
RA Gremer L., Merbitz-Zahradnik T., Dvorsky R., Cirstea I.C., Kratz C.P.,
RA Zenker M., Wittinghofer A., Ahmadian M.R.;
RT "Germline KRAS mutations cause aberrant biochemical and physical
RT properties leading to developmental disorders.";
RL Hum. Mutat. 32:33-43(2011).
RN [37]
RP VARIANTS CFC2 HIS-71 AND GLU-147.
RX PubMed=21797849; DOI=10.1111/j.1399-0004.2011.01754.x;
RA Stark Z., Gillessen-Kaesbach G., Ryan M.M., Cirstea I.C., Gremer L.,
RA Ahmadian M.R., Savarirayan R., Zenker M.;
RT "Two novel germline KRAS mutations: expanding the molecular and
RT clinical phenotype.";
RL Clin. Genet. 81:590-594(2012).
CC -!- FUNCTION: Ras proteins bind GDP/GTP and possess intrinsic GTPase
CC activity.
CC -!- ENZYME REGULATION: Alternates between an inactive form bound to
CC GDP and an active form bound to GTP. Activated by a guanine
CC nucleotide-exchange factor (GEF) and inactivated by a GTPase-
CC activating protein (GAP).
CC -!- SUBUNIT: Interacts with PHLPP. Interacts (active GTP-bound form
CC preferentially) with RGS14 (By similarity).
CC -!- INTERACTION:
CC Q04631:Fnta (xeno); NbExp=2; IntAct=EBI-367427, EBI-602447;
CC P04049:RAF1; NbExp=2; IntAct=EBI-367427, EBI-365996;
CC P50749:RASSF2; NbExp=2; IntAct=EBI-367415, EBI-960081;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic
CC side.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Comment=Isoforms differ in the C-terminal region which is
CC encoded by two alternative exons (IVA and IVB);
CC Name=2A; Synonyms=K-Ras4A;
CC IsoId=P01116-1; Sequence=Displayed;
CC Name=2B; Synonyms=K-Ras4B;
CC IsoId=P01116-2, P01118-1;
CC Sequence=VSP_011140, VSP_011141;
CC Note=Variant in position: 152:V->G (in NS3). Variant in
CC position: 153:D->V (in CFC2 and NS3, exhibits only minor
CC alterations in its in vitro biochemical behavior compared to
CC wild-type protein). Variant in position: 156:F->I (in NS3/CFC2).
CC Variant in position: 156:F->L (found in a patient with Costello
CC syndrome, exhibits an increase in intrinsic and guanine
CC nucleotide exchange factor catalyzed nucleotide exchange in
CC combination with an impaired GTPase-activating
CC protein-stimulated GTP hydrolysis but functional in interaction
CC with effectors);
CC -!- PTM: Acetylation at Lys-104 prevents interaction with guanine
CC nucleotide exchange factors (GEFs).
CC -!- DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype
CC of acute leukemia, a cancer of the white blood cells. AML is a
CC malignant disease of bone marrow characterized by maturational
CC arrest of hematopoietic precursors at an early stage of
CC development. Clonal expansion of myeloid blasts occurs in bone
CC marrow, blood, and other tissue. Myelogenous leukemias develop
CC from changes in cells that normally produce neutrophils,
CC basophils, eosinophils and monocytes. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An
CC aggressive pediatric myelodysplastic syndrome/myeloproliferative
CC disorder characterized by malignant transformation in the
CC hematopoietic stem cell compartment with proliferation of
CC differentiated progeny. Patients have splenomegaly, enlarged lymph
CC nodes, rashes, and hemorrhages. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Noonan syndrome 3 (NS3) [MIM:609942]: A form of Noonan
CC syndrome, a disease characterized by short stature, facial
CC dysmorphic features such as hypertelorism, a downward eyeslant and
CC low-set posteriorly rotated ears, and a high incidence of
CC congenital heart defects and hypertrophic cardiomyopathy. Other
CC features can include a short neck with webbing or redundancy of
CC skin, deafness, motor delay, variable intellectual deficits,
CC multiple skeletal defects, cryptorchidism, and bleeding diathesis.
CC Individuals with Noonan syndrome are at risk of juvenile
CC myelomonocytic leukemia, a myeloproliferative disorder
CC characterized by excessive production of myelomonocytic cells.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Gastric cancer (GASC) [MIM:613659]: A malignant disease
CC which starts in the stomach, can spread to the esophagus or the
CC small intestine, and can extend through the stomach wall to nearby
CC lymph nodes and organs. It also can metastasize to other parts of
CC the body. The term gastric cancer or gastric carcinoma refers to
CC adenocarcinoma of the stomach that accounts for most of all
CC gastric malignant tumors. Two main histologic types are
CC recognized, diffuse type and intestinal type carcinomas. Diffuse
CC tumors are poorly differentiated infiltrating lesions, resulting
CC in thickening of the stomach. In contrast, intestinal tumors are
CC usually exophytic, often ulcerating, and associated with
CC intestinal metaplasia of the stomach, most often observed in
CC sporadic disease. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=Defects in KRAS are a cause of pylocytic astrocytoma
CC (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal
CC cord derived from glial cells which vary from histologically
CC benign forms to highly anaplastic and malignant tumors.
CC -!- DISEASE: Cardiofaciocutaneous syndrome 2 (CFC2) [MIM:615278]: A
CC form of cardiofaciocutaneous syndrome, a multiple congenital
CC anomaly disorder characterized by a distinctive facial appearance,
CC heart defects and mental retardation. Heart defects include
CC pulmonic stenosis, atrial septal defects and hypertrophic
CC cardiomyopathy. Some affected individuals present with ectodermal
CC abnormalities such as sparse, friable hair, hyperkeratotic skin
CC lesions and a generalized ichthyosis-like condition. Typical
CC facial features are similar to Noonan syndrome. They include high
CC forehead with bitemporal constriction, hypoplastic supraorbital
CC ridges, downslanting palpebral fissures, a depressed nasal bridge,
CC and posteriorly angulated ears with prominent helices. CFC2
CC patients often do not have the skin abnormalities, such as
CC ichthyosis, hyperkeratosis, and hemangioma observed in CFC1.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Note=KRAS mutations are involved in cancer development.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/KRASID91.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/KRAS";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=KRAS";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; L00049; AAB59444.1; -; Genomic_DNA.
DR EMBL; L00045; AAB59444.1; JOINED; Genomic_DNA.
DR EMBL; L00046; AAB59444.1; JOINED; Genomic_DNA.
DR EMBL; L00047; AAB59444.1; JOINED; Genomic_DNA.
DR EMBL; L00048; AAB59445.1; -; Genomic_DNA.
DR EMBL; L00045; AAB59445.1; JOINED; Genomic_DNA.
DR EMBL; L00046; AAB59445.1; JOINED; Genomic_DNA.
DR EMBL; L00047; AAB59445.1; JOINED; Genomic_DNA.
DR EMBL; M54968; AAB41942.1; -; mRNA.
DR EMBL; AF493917; AAM12631.1; -; mRNA.
DR EMBL; BT007153; AAP35817.1; -; mRNA.
DR EMBL; AK292510; BAF85199.1; -; mRNA.
DR EMBL; CH471094; EAW96511.1; -; Genomic_DNA.
DR EMBL; CH471094; EAW96512.1; -; Genomic_DNA.
DR EMBL; EU332849; ABY87538.1; -; Genomic_DNA.
DR EMBL; BC013572; AAH13572.1; -; mRNA.
DR EMBL; K01519; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; K01520; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M25876; AAA35683.1; -; Genomic_DNA.
DR EMBL; M34904; AAA36149.1; -; Genomic_DNA.
DR EMBL; M30539; AAA36557.1; -; Genomic_DNA.
DR EMBL; X01669; CAA25828.1; -; Genomic_DNA.
DR EMBL; X02825; CAA26593.1; -; Genomic_DNA.
DR EMBL; K03210; AAA36554.1; -; Genomic_DNA.
DR EMBL; K03209; AAA36554.1; JOINED; Genomic_DNA.
DR PIR; A93311; TVHUK.
DR PIR; B93311; TVHU2K.
DR RefSeq; NP_004976.2; NM_004985.3.
DR RefSeq; NP_203524.1; NM_033360.2.
DR RefSeq; XP_005253422.1; XM_005253365.1.
DR UniGene; Hs.37003; -.
DR UniGene; Hs.505033; -.
DR PDB; 1D8D; X-ray; 2.00 A; P=169-173.
DR PDB; 1D8E; X-ray; 3.00 A; P=169-173.
DR PDB; 1KZO; X-ray; 2.20 A; C=169-173.
DR PDB; 1KZP; X-ray; 2.10 A; C=169-173.
DR PDB; 3GFT; X-ray; 2.27 A; A/B/C/D/E/F=1-164.
DR PDB; 4DSN; X-ray; 2.03 A; A=2-164.
DR PDB; 4DSO; X-ray; 1.85 A; A=2-164.
DR PDB; 4EPR; X-ray; 2.00 A; A=1-164.
DR PDB; 4EPT; X-ray; 2.00 A; A=1-164.
DR PDB; 4EPV; X-ray; 1.35 A; A=1-164.
DR PDB; 4EPW; X-ray; 1.70 A; A=1-164.
DR PDB; 4EPX; X-ray; 1.76 A; A=1-164.
DR PDB; 4EPY; X-ray; 1.80 A; A=1-164.
DR PDBsum; 1D8D; -.
DR PDBsum; 1D8E; -.
DR PDBsum; 1KZO; -.
DR PDBsum; 1KZP; -.
DR PDBsum; 3GFT; -.
DR PDBsum; 4DSN; -.
DR PDBsum; 4DSO; -.
DR PDBsum; 4EPR; -.
DR PDBsum; 4EPT; -.
DR PDBsum; 4EPV; -.
DR PDBsum; 4EPW; -.
DR PDBsum; 4EPX; -.
DR PDBsum; 4EPY; -.
DR ProteinModelPortal; P01116; -.
DR SMR; P01116; 1-166.
DR DIP; DIP-33951N; -.
DR IntAct; P01116; 20.
DR MINT; MINT-131580; -.
DR STRING; 9606.ENSP00000256078; -.
DR ChEMBL; CHEMBL2189121; -.
DR PhosphoSite; P01116; -.
DR DMDM; 131875; -.
DR PaxDb; P01116; -.
DR PeptideAtlas; P01116; -.
DR PRIDE; P01116; -.
DR DNASU; 3845; -.
DR Ensembl; ENST00000256078; ENSP00000256078; ENSG00000133703.
DR Ensembl; ENST00000311936; ENSP00000308495; ENSG00000133703.
DR GeneID; 3845; -.
DR KEGG; hsa:3845; -.
DR UCSC; uc001rgp.1; human.
DR CTD; 3845; -.
DR GeneCards; GC12M025358; -.
DR HGNC; HGNC:6407; KRAS.
DR MIM; 190070; gene.
DR MIM; 601626; phenotype.
DR MIM; 607785; phenotype.
DR MIM; 609942; phenotype.
DR MIM; 613659; phenotype.
DR MIM; 615278; phenotype.
DR neXtProt; NX_P01116; -.
DR Orphanet; 1340; Cardiofaciocutaneous syndrome.
DR Orphanet; 3071; Costello syndrome.
DR Orphanet; 1333; Familial pancreatic carcinoma.
DR Orphanet; 86834; Juvenile myelomonocytic leukemia.
DR Orphanet; 2612; Linear nevus sebaceus syndrome.
DR Orphanet; 648; Noonan syndrome.
DR Orphanet; 357194; Selection of therapeutic option in colorectal cancer.
DR Orphanet; 357191; Selection of therapeutic option in non-small cell lung carcinoma.
DR PharmGKB; PA30196; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P01116; -.
DR KO; K07827; -.
DR OMA; RRYNREM; -.
DR OrthoDB; EOG7QVM41; -.
DR PhylomeDB; P01116; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P01116; -.
DR ChiTaRS; KRAS; human.
DR EvolutionaryTrace; P01116; -.
DR GeneWiki; KRAS; -.
DR GenomeRNAi; 3845; -.
DR NextBio; 15131; -.
DR PRO; PR:P01116; -.
DR ArrayExpress; P01116; -.
DR Bgee; P01116; -.
DR CleanEx; HS_KRAS; -.
DR Genevestigator; P01116; -.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0019003; F:GDP binding; IEA:Ensembl.
DR GO; GO:0019002; F:GMP binding; IEA:Ensembl.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IEA:Ensembl.
DR GO; GO:0030036; P:actin cytoskeleton organization; IEA:Ensembl.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:BHF-UCL.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IEA:Ensembl.
DR GO; GO:0051000; P:positive regulation of nitric-oxide synthase activity; IEA:Ensembl.
DR GO; GO:0035022; P:positive regulation of Rac protein signal transduction; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:0048169; P:regulation of long-term neuronal synaptic plasticity; IEA:Ensembl.
DR GO; GO:0032228; P:regulation of synaptic transmission, GABAergic; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0051385; P:response to mineralocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0035176; P:social behavior; IEA:Ensembl.
DR GO; GO:0051146; P:striated muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0008542; P:visual learning; IEA:Ensembl.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00173; RAS; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cardiomyopathy;
KW Cell membrane; Complete proteome; Deafness; Direct protein sequencing;
KW Disease mutation; Ectodermal dysplasia; GTP-binding; Lipoprotein;
KW Membrane; Mental retardation; Methylation; Nucleotide-binding;
KW Palmitate; Polymorphism; Prenylation; Proto-oncogene;
KW Reference proteome.
FT CHAIN 1 186 GTPase KRas.
FT /FTId=PRO_0000082641.
FT INIT_MET 1 1 Removed; alternate.
FT CHAIN 2 186 GTPase KRas, N-terminally processed.
FT /FTId=PRO_0000326480.
FT PROPEP 187 189 Removed in mature form.
FT /FTId=PRO_0000281291.
FT NP_BIND 10 17 GTP.
FT NP_BIND 57 61 GTP.
FT NP_BIND 116 119 GTP.
FT REGION 166 185 Hypervariable region.
FT MOTIF 32 40 Effector region.
FT MOD_RES 1 1 N-acetylmethionine; in GTPase KRas;
FT alternate.
FT MOD_RES 2 2 N-acetylthreonine; in GTPase KRas, N-
FT terminally processed.
FT MOD_RES 104 104 N6-acetyllysine.
FT MOD_RES 186 186 Cysteine methyl ester.
FT LIPID 180 180 S-palmitoyl cysteine.
FT LIPID 186 186 S-farnesyl cysteine.
FT VAR_SEQ 151 153 RVE -> GVD (in isoform 2B).
FT /FTId=VSP_011140.
FT VAR_SEQ 165 189 QYRLKKISKEEKTPGCVKIKKCIIM -> KHKEKMSKDGKK
FT KKKKSKTKCVIM (in isoform 2B).
FT /FTId=VSP_011141.
FT VARIANT 5 5 K -> E (in NS3).
FT /FTId=VAR_065144.
FT VARIANT 5 5 K -> N (in GASC; found also in a patient
FT with Costello syndrome; exhibits only
FT minor alterations in its in vitro
FT biochemical behavior compared to wild-
FT type protein).
FT /FTId=VAR_064849.
FT VARIANT 10 10 G -> GG (in one individual with AML;
FT expression in 3T3 cell causes cellular
FT transformation; expression in COS cells
FT activates the Ras-MAPK signaling pathway;
FT lower GTPase activity; faster GDP
FT dissociation rate).
FT /FTId=VAR_034601.
FT VARIANT 12 12 G -> A (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036305.
FT VARIANT 12 12 G -> C (in lung carcinoma; somatic
FT mutation).
FT /FTId=VAR_006839.
FT VARIANT 12 12 G -> D (in pancreatic carcinoma, GASC and
FT lung carcinoma; somatic mutation).
FT /FTId=VAR_016026.
FT VARIANT 12 12 G -> R (in lung cancer and bladder
FT cancer; somatic mutation).
FT /FTId=VAR_016027.
FT VARIANT 12 12 G -> S (in lung carcinoma and GASC;
FT somatic mutation).
FT /FTId=VAR_016028.
FT VARIANT 12 12 G -> V (in lung carcinoma, pancreatic
FT carcinoma, colon cancer and GASC; somatic
FT mutation, constitutively activated).
FT /FTId=VAR_006840.
FT VARIANT 13 13 G -> D (in a breast carcinoma cell line
FT and GASC; somatic mutation).
FT /FTId=VAR_016029.
FT VARIANT 13 13 G -> R (in pylocytic astrocytoma; somatic
FT mutation; increase activation of the Ras
FT pathway).
FT /FTId=VAR_065145.
FT VARIANT 14 14 V -> I (in NS3; affects activity and
FT impairs responsiveness to GTPase
FT activating proteins; characterized by a
FT strong increase of both intrinsic and
FT guanine nucleotide exchanged factor-
FT catalyzed nucleotide exchange leading to
FT an increased level of the activated
FT state).
FT /FTId=VAR_026109.
FT VARIANT 22 22 Q -> E (in CFC2; exhibits an increase in
FT intrinsic and guanine nucleotide exchange
FT factor catalyzed nucleotide exchange in
FT combination with an impaired GTPase-
FT activating protein-stimulated GTP
FT hydrolysis but functional in interaction
FT with effectors).
FT /FTId=VAR_064850.
FT VARIANT 22 22 Q -> R (in NS3; impairs GTPase-activating
FT protein stimulated GTP hydrolysis with
FT unaffected intrinsic functions and a
FT virtually functional effector
FT interaction).
FT /FTId=VAR_064851.
FT VARIANT 34 34 P -> L (in NS3; characterized by a
FT defective GTPase-activating protein
FT sensitivity and a strongly reduced
FT interaction with effectors).
FT /FTId=VAR_064852.
FT VARIANT 34 34 P -> Q (in NS3).
FT /FTId=VAR_064853.
FT VARIANT 34 34 P -> R (in CFC2; characterized by a
FT defective GTPase-activating protein
FT sensitivity and a strongly reduced
FT interaction with effectors).
FT /FTId=VAR_026110.
FT VARIANT 36 36 I -> M (in NS3).
FT /FTId=VAR_064854.
FT VARIANT 58 58 T -> I (in NS3; affects activity and
FT impairs responsiveness to GTPase
FT activating proteins; exhibits only minor
FT alterations in its in vitro biochemical
FT behavior compared to wild-type protein).
FT /FTId=VAR_026111.
FT VARIANT 59 59 A -> T (in bladder cancer and GASC;
FT somatic mutation).
FT /FTId=VAR_016030.
FT VARIANT 60 60 G -> R (in CFC2; characterized by a
FT defective GTPase-activating protein
FT sensitivity and a strongly reduced
FT interaction with effectors).
FT /FTId=VAR_026112.
FT VARIANT 60 60 G -> S (in NS3).
FT /FTId=VAR_065146.
FT VARIANT 61 61 Q -> H (in lung carcinoma;
FT dbSNP:rs17851045).
FT /FTId=VAR_006841.
FT VARIANT 61 61 Q -> R (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036306.
FT VARIANT 71 71 Y -> H (in CFC2).
FT /FTId=VAR_069784.
FT VARIANT 117 117 K -> N (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036307.
FT VARIANT 146 146 A -> T (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036308.
FT VARIANT 147 147 K -> E (in CFC2).
FT /FTId=VAR_069785.
FT MUTAGEN 164 164 R->A: Loss of GTP-binding activity.
FT STRAND 3 9
FT HELIX 16 25
FT STRAND 38 46
FT STRAND 49 57
FT HELIX 65 74
FT STRAND 76 83
FT HELIX 87 104
FT STRAND 111 116
FT STRAND 120 122
FT HELIX 127 137
FT STRAND 141 143
FT TURN 146 148
FT HELIX 152 164
SQ SEQUENCE 189 AA; 21656 MW; 973547B2E11C2C81 CRC64;
MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG
QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDL
PSRTVDTKQA QDLARSYGIP FIETSAKTRQ RVEDAFYTLV REIRQYRLKK ISKEEKTPGC
VKIKKCIIM
//

MIM 190070
*RECORD*
*FIELD* NO
190070
*FIELD* TI
*190070 V-KI-RAS2 KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG; KRAS
;;ONCOGENE KRAS2; KRAS2;;
read moreKIRSTEN MURINE SARCOMA VIRUS 2; RASK2;;
C-KRAS
V-KI-RAS1 PSEUDOGENE, INCLUDED; KRAS1P, INCLUDED;;
ONCOGENE KRAS1, INCLUDED; KRAS1, INCLUDED;;
KIRSTEN RAS1, INCLUDED; RASK1, INCLUDED
*FIELD* TX

DESCRIPTION

The KRAS gene encodes the human cellular homolog of a transforming gene
isolated from the Kirsten rat sarcoma virus. The RAS proteins are
GDP/GTP-binding proteins that act as intracellular signal transducers.
The most well-studied members of the RAS (derived from 'RAt Sarcoma'
virus) gene family include KRAS, HRAS (190020), and NRAS (164790). These
genes encode immunologically related proteins with a molecular mass of
21 kD and are homologs of rodent sarcoma virus genes that have
transforming abilities. While these wildtype cellular proteins in humans
play a vital role in normal tissue signaling, including proliferation,
differentiation, and senescence, mutated genes are potent oncogenes that
play a role in many human cancers (Weinberg, 1982; Kranenburg, 2005).

CLONING

Der et al. (1982) identified a new human DNA sequence homologous to the
transforming oncogene of the Kirsten (ras-K) murine sarcoma virus within
mouse 3T3 fibroblast cells transformed by DNA from an undifferentiated
human lung cancer cell line (LX-1). The findings showed that KRAS could
act as an oncogene in human cancer.

Chang et al. (1982) isolated clones corresponding to the human cellular
KRAS gene from human placental and embryonic cDNA libraries. Two
isoforms were identified, designated KRAS1 and KRAS2. KRAS1 contained
0.9 kb homologous to viral Kras and had 1 intervening sequence, and
KRAS2 contained 0.3 kb homologous to viral Kras. McCoy et al. (1983)
characterized the KRAS gene isolated from a human colon adenocarcinoma
cell line (SW840) and determined that it corresponded to KRAS2 as
identified by Chang et al. (1982). The KRAS2 oncogene was amplified in
several tumor cell lines.

McGrath et al. (1983) cloned the KRAS1 and KRAS2 genes and determined
that the KRAS1 gene is a pseudogene. The KRAS2 gene encodes a
188-residue protein with a molecular mass of 21.66 kD. It showed only 6
amino acid differences from the viral gene. Comparison of the 2 KRAS
genes showed that KRAS1 is lacking several intervening sequences,
consistent with it being a pseudogene derived from a processed KRAS2
mRNA. The major KRAS2 mRNA transcript is 5.5 kb. Alternative splicing
results in 2 variants, isoforms A and B, that differ in the C-terminal
region.

Alternative splicing of exon 5 results in the KRASA and KRASB isoforms.
Exon 6 contains the C-terminal region in KRASB, whereas it encodes the
3-prime untranslated region in KRASA. The differing C-terminal regions
of these isoforms are subjected to posttranslational modifications. The
differential posttranslational processing has profound functional
effects leading to alternative trafficking pathways and protein
localization (Carta et al., 2006).

GENE STRUCTURE

McGrath et al. (1983) first reported that the KRAS2 gene spans 38 kb and
contains 4 exons. Detailed sequence analysis showed that exon 4 has 2
forms, which the authors designated 4A and 4B.

The KRAS2 gene has been shown to have a total of 6 exons. Exons 2, 3,
and 4 are invariant coding exons, whereas exon 5 undergoes alternative
splicing. KRASB results from exon 5 skipping. In KRASA mRNA, exon 6
encodes the 3-prime untranslated region. In KRASB mRNA, exon 6 encodes
the C-terminal region (Carta et al., 2006).

MAPPING

By in situ hybridization, Popescu et al. (1985) mapped the KRAS2 gene to
chromosome 12p12.1-p11.1. By linkage with RFLPs, O'Connell et al. (1985)
confirmed the approximate location of KRAS2 on 12p12.1.

- Pseudogene

The KRAS1 gene is a KRAS2 pseudogene and has been assigned to chromosome
6 (O'Brien et al., 1983; McBride et al., 1983). By in situ
hybridization, Popescu et al. (1985) assigned the KRAS1 gene to
6p12-p11. Because KRAS1 was found to be a pseudogene, its official
symbol was changed to KRAS1P.

GENE FUNCTION

Johnson et al. (2005) found that the 3 human RAS genes, HRAS, KRAS, and
NRAS, contain multiple let-7 (605386) complementary sites in their
3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7
expression was lower in lung tumors than in normal lung tissue, whereas
expression of the RAS proteins was significantly higher in lung tumors,
suggesting a possible mechanism for let-7 in cancer.

Bivona et al. (2006) found that the subcellular localization and
function of Kras in mammalian cells was modulated by Pkc (see 176960).
Phosphorylation of Kras by Pkc agonists induced rapid translocation of
Kras from the plasma membrane to several intracellular membranes,
including the outer mitochondrial membrane, where Kras associated with
Bclxl (BCL2L1; 600039). Phosphorylated Kras required Bclxl for induction
of apoptosis.

Yeung et al. (2006) devised genetically encoded probes to assess surface
potential in intact cells. These probes revealed marked, localized
alterations in the change of the inner surface of the plasma membrane of
macrophages during the course of phagocytosis. Hydrolysis of
phosphoinositides and displacement of phosphatidylserine accounted for
the change in surface potential at the phagosomal cup. Signaling
molecules such as KRAS, RAC1 (602048), and c-SRC (190090) that are
targeted to the membrane by electrostatic interactions were rapidly
released from membrane subdomains where the surface charge was altered
by lipid remodeling during phagocytosis.

Heo et al. (2006) surveyed plasma membrane targeting mechanisms by
imaging the subcellular localization of 125 fluorescent
protein-conjugated Ras, Rab, Arf, and Rho proteins. Of 48 proteins that
were localized to the plasma membrane, 37 contained clusters of
positively charged amino acids. To test whether these polybasic clusters
bind negatively charged phosphatidylinositol 4,5-bisphosphate lipids,
Heo et al. (2006) developed a chemical phosphatase activation method to
deplete plasma membrane phosphatidylinositol 4,5-bisphosphate.
Unexpectedly, proteins with polybasic clusters dissociated from the
plasma membrane only when both phosphatidylinositol 4,5-bisphosphate and
phosphatidylinositol 3,4,5-trisphosphate were depleted, arguing that
both lipid second messengers jointly regulate plasma membrane targeting.

Gazin et al. (2007) performed a genomewide RNA interference (RNAi)
screen in KRAS-transformed NIH 3T3 cells and identified 28 genes
required for RAS-mediated epigenetic silencing of the proapoptotic FAS
gene (TNFRSF6; 134637). At least 9 of these RAS epigenetic silencing
effectors (RESEs), including the DNA methyltransferase DNMT1 (126375),
were directly associated with specific regions of the FAS promoter in
KRAS-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells.
RNAi-mediated knockdown of any of the 28 RESEs resulted in failure to
recruit DNMT1 to the FAS promoter, loss of FAS promoter
hypermethylation, and derepression of FAS expression. Analysis of 5
other epigenetically repressed genes indicated that RAS directs the
silencing of multiple unrelated genes through a largely common pathway.
Finally, Gazin et al. (2007) showed that 9 RESEs are required for
anchorage-independent growth and tumorigenicity of KRAS-transformed NIH
3T3 cells; these 9 genes had not previously been implicated in
transformation by RAS. Gazin et al. (2007) concluded that RAS-mediated
epigenetic silencing occurs through a specific, complex pathway
involving components that are required for maintenance of a fully
transformed phenotype.

Haigis et al. (2008) used genetically engineered mice to determine
whether and how the related oncogenes Kras and Nras (164790) regulate
homeostasis and tumorigenesis in the colon. Expression of Kras(G12D) in
the colonic epithelium stimulated hyperproliferation in a Mek (see
176872)-dependent manner. Nras(G12D) did not alter the growth properties
of the epithelium, but was able to confer resistance to apoptosis. In
the context of an Apc (611731)-mutant colonic tumor, activation of Kras
led to defects in terminal differentiation and expansion of putative
stem cells within the tumor epithelium. This Kras tumor phenotype was
associated with attenuated signaling through the MAPK pathway, and human
colon cancer cells expressing mutant Kras were hypersensitive to
inhibition of Raf (see 164760) but not Mek. Haigis et al. (2008)
concluded that their studies demonstrated clear phenotypic differences
between mutant Kras and Nras, and suggested that the oncogenic phenotype
of mutant Kras might be mediated by noncanonical signaling through Ras
effector pathways.

By studying the transcriptomes of paired colorectal cancer cell lines
that differed only in the mutational status of their KRAS or BRAF
(164757) genes, Yun et al. (2009) found that GLUT1 (138140), encoding
glucose transporter-1, was 1 of 3 genes consistently upregulated in
cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced
glucose uptake and glycolysis and survived in low-glucose conditions,
phenotypes that all required GLUT1 expression. In contrast, when cells
with wildtype KRAS alleles were subjected to a low-glucose environment,
very few cells survived. Most surviving cells expressed high levels of
GLUT1, and 4% of these survivors had acquired KRAS mutations not present
in their parents. The glycolysis inhibitor 3-bromopyruvate
preferentially suppressed the growth of cells with KRAS or BRAF
mutations. Yun et al. (2009) concluded that, taken together, these data
suggested that glucose deprivation can drive the acquisition of KRAS
pathway mutations in human tumors.

Meylan et al. (2009) showed that the NF-kappa-B (see 164011) pathway is
required for the development of tumors in a mouse model of lung
adenocarcinoma. Concomitant loss of p53 (191170) and expression of
oncogenic Kras containing the G12D mutation resulted in NF-kappa-B
activation in primary mouse embryonic fibroblasts. Conversely, in lung
tumor cell lines expressing Kras(G12D) and lacking p53, p53 restoration
led to NF-kappa-B inhibition. Furthermore, the inhibition of NF-kappa-B
signaling induced apoptosis in p53-null lung cancer cell lines.
Inhibition of the pathway in lung tumors in vivo, from the time of tumor
initiation or after tumor progression, resulted in significantly reduced
tumor development. Meylan et al. (2009) concluded that, together, their
results indicated a critical function for NF-kappa-B signaling in lung
tumor development and, further, that this requirement depends on p53
status.

Barbie et al. (2009) used systematic RNA interference to detect
synthetic lethal partners of oncogenic KRAS and found that the
noncanonical I-kappa-B kinase TBK1 (604834) was selectively essential in
cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis
specifically in human cancer cell lines that depend on oncogenic KRAS
expression. In these cells, TBK1 activated NF-kappa-B antiapoptotic
signals involving c-REL (164910) and BCLXL (BCL2L1; 600039) that were
essential for survival, providing mechanistic insights into this
synthetic lethal interaction. Barbie et al. (2009) concluded that TBK1
and NF-kappa-B signaling are essential in KRAS mutant tumors, and
establish a general approach for the rational identification of
codependent pathways in cancer.

In Drosophila eye-antennal discs, cooperation between Ras(V12), an
oncogenic form of the Ras85D protein, and loss-of-function mutations in
the conserved tumor suppressor 'scribble' (607733) gives rise to
metastatic tumors that display many characteristics observed in human
cancers (summary by Wu et al., 2010). Wu et al. (2010) showed that
clones of cells bearing different mutations can cooperate to promote
tumor growth and invasion in Drosophila. The authors found that the
Ras(V12) and scrib-null mutations can also cause tumors when they affect
different adjacent epithelial cells. Wu et al. (2010) showed that this
interaction between Ras(V12) and scrib-null clones involves JNK
signaling propagation and JNK-induced upregulation of
JAK/STAT-activating cytokines (see 604260), a compensatory growth
mechanism for tissue homeostasis. The development of Ras(V12) tumors can
also be triggered by tissue damage, a stress condition that activates
JNK signaling. The authors suggested that similar cooperative mechanisms
could have a role in the development of human cancers.

Correct localization and signaling by farnesylated KRAS is regulated by
the prenyl-binding protein PDE-delta (PDED; 602676), which sustains the
spatial organization of KRAS by facilitating its diffusion in the
cytoplasm (Chandra et al., 2012; Zhang et al., 2004). Zimmerman et al.
(2013) reported that interfering with the binding of mammalian PDED to
KRAS by means of small molecules provided a novel opportunity to
suppress oncogenic RAS signaling by altering its localization to
endomembranes. Biochemical screening and subsequent structure-based hit
optimization yielded inhibitors of the KRAS-PDED interaction that
selectively bound to the prenyl-binding pocket of PDED with nanomolar
affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and
in vivo proliferation of human pancreatic ductal adenocarcinoma cells
that are dependent on oncogenic KRAS.

- Regulation of KRAS Expression by KRAS1P Transcript Levels

Following their finding that PTENP1 (613531), a pseudogene of the PTEN
(601728) tumor suppressor gene, can derepress PTEN by acting as a decoy
for PTEN-targeting miRNAS, Poliseno et al. (2010) extended their
analysis to the oncogene KRAS and its pseudogene KRAS1. KRAS1P 3-prime
UTR overexpression in DU145 prostate cancer cells resulted in increased
KRAS mRNA abundance and accelerated cell growth. They also found that
KRAS and KRAS1P transcript levels were positively correlated in prostate
cancer. Notably, the KRAS1P locus 6p12-p11 is amplified in different
human tumors, including neuroblastoma, retinoblastoma, and
hepatocellular carcinoma. Poliseno et al. (2010) concluded that their
findings together pointed to a putative protooncogenic role for KRAS1P,
and supported the notion that pseudogene functions mirror the functions
of their cognate genes as explained by a miRNA decoy mechanism.

MOLECULAR GENETICS

- Role in Solid Tumors

KRAS is said to be one of the most activated oncogenes, with 17 to 25%
of all human tumors harboring an activating KRAS mutation (Kranenburg,
2005). Critical regions of the KRAS gene for oncogenic activation
include codons 12, 13, 59, 61, and 63 (Grimmond et al., 1992). These
activating mutations cause Ras to accumulate in the active GTP-bound
state by impairing intrinsic GTPase activity and conferring resistance
to GTPase activating proteins (Zenker et al., 2007).

In a study of 96 human tumors or tumor cell lines in the NIH 3T3
transforming system, Pulciani et al. (1982) found a mutated HRAS locus
only in a single cancer cell line, whereas transforming KRAS genes were
identified in 8 different carcinomas and sarcomas. KRAS appeared to be
involved in malignancy much more often than HRAS. In a serous
cystadenocarcinoma of the ovary (167000), Feig et al. (1984) showed the
presence of an activated KRAS oncogene that was not activated in normal
cells of the same patient. The transforming gene product displayed an
electrophoretic mobility pattern that differed from that of KRAS
transforming proteins in other tumors, suggesting a novel somatic KRAS
mutation in this tumor.

In a cell line of human lung cancer (211980), Nakano et al. (1984)
identified a mutation in the KRAS2 gene (190070.0001), resulting in gene
activation with transforming ability of the mutant protein.

Rodenhuis et al. (1987) used a novel, highly sensitive assay based on
oligonucleotide hybridization following in vitro amplification to
examine DNA from 39 lung tumor specimens. The KRAS gene was found to be
activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two
of these tumors were less than 2 cm in size and had not metastasized. No
HRAS, KRAS, or NRAS mutations were observed in 15 squamous cell
carcinomas, 10 large cell carcinomas, 1 carcinoid tumor, 2 metastatic
adenocarcinomas from primary tumors outside the lung, and 1 small cell
carcinoma. An approximately 20-fold amplification of the unmutated KRAS
gene was observed in a tumor that proved to be a solitary lung
metastasis of a rectal carcinoma.

Yanez et al. (1987) found mutations in codon 12 of the KRAS gene in 4 of
16 colon cancers (114500), 2 of 27 lung cancers, and 1 of 8 breast
cancers (114480); no mutations were found at codon position 61.

The highest observed frequency of KRAS2 point mutations occurs in
pancreatic carcinomas (260350), with 90% of the patients having at least
1 KRAS2 mutation (Almoguera et al., 1988; Smit et al., 1988). Most of
these mutations are in codon 12 (see, e.g., G12D, 190070.0005 and G12V,
190070.0006) (Hruban et al., 1993).

Burmer and Loeb (1989) identified KRAS2 mutations in both diploid and
aneuploid cells in colon adenomas and carcinomas. Twenty-six of 40 colon
carcinomas contained mutations at codon 12, and 9 of the 12 adenomas
studied contained similar mutations.

Sidransky et al. (1992) found that KRAS mutations were detectable in DNA
purified from stool in 8 of 9 patients with colorectal tumors that
contained KRAS mutations. Takeda et al. (1993) used a
mutant-allele-specific amplification (MASA) method to detect KRAS
mutations in cells obtained from the sputum of patients with lung
cancer. A mutation was found in 1 of 5 patients studied. The authors
suggested that the MASA system could be applied to an examination of
metastatic lung carcinomas, particularly from adenocarcinomas of the
colon and pancreas in which KRAS mutations are frequently detected, and
to mass screening for colorectal tumors, using DNA isolated from feces
as a template.

Lee et al. (1995) identified mutations in codon 12 of the KRAS gene in
11 (7.9%) of 140 gastric cancers (137215). Seven cases had a G12S
mutation (190070.0007) and 2 had a G12D mutation (190070.0005). Tumors
located in the upper third of the stomach had a significantly higher
frequency of KRAS codon 12 mutations (3 of 8; 37.5%) compared with
tumors located in the middle (4 of 29; 13.8%) or lower (3 of 99; 3%)
thirds of the stomach (P = 0.001). Among 8 patients with stomach cancer
located in the upper part of the stomach, death occurred in 4 of 5
patients with tumors without KRAS gene mutations, but in none of the 3
patients with KRAS gene-mutated tumors.

Otori et al. (1997) examined tissue sections from 19 hyperplastic
colorectal polyps for mutations in exons 12 and 13 of the KRAS gene.
KRAS mutations were detected in 9 (47%) of 19 polyps, suggesting that
some hyperplastic colorectal polyps may be true premalignant lesions.

KRAS activation has been recognized in microdissected foci of pancreatic
intraepithelial neoplasia (Cubilla and Fitzgerald, 1976; Hruban et al.,
2000; Hruban et al., 2000), the candidate precursor lesion of pancreatic
cancer previously known as ductal cell hyperplasia. Laghi et al. (2002)
found that KRAS codon 12 was mutated in 34 of 41 (83%) pancreatic
cancers and in 11 of 13 (85%) biliary cancers. Multiple distinct KRAS
mutations were found in 16 pancreatic cancers and in 8 biliary cancers.
Multiple KRAS mutations were more frequent in cancers with detectable
pancreatic intraepithelial neoplasia than in those without, and
individual precursor lesions of the same neoplastic pancreas harbored
distinct mutations. The results indicated that clonally distinct
precursor lesions of pancreatic cancer may variably contribute to tumor
development.

Nikiforova et al. (2003) analyzed a series of 88 conventional follicular
(188470) and Hurthle cell (607464) thyroid tumors for HRAS, NRAS, or
KRAS mutations and PAX8 (167415)-PPARG (601487) rearrangements.
Forty-nine percent of conventional follicular carcinomas had RAS
mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both.
Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG
rearrangement, and 48% had neither. Hurthle cell tumors infrequently had
PAX8-PPARG rearrangement or RAS mutations.

Rajagopalan et al. (2002) systematically evaluated mutations in the BRAF
(164757) and KRAS genes in 330 colorectal tumors. There were 32
mutations in BRAF and 169 mutations in KRAS; no tumor exhibited
mutations in both BRAF and KRAS. Rajagopalan et al. (2002) concluded
that BRAF and KRAS mutations are equivalent in their tumorigenic effects
and are mutated at a similar phase of tumorigenesis, after initiation
but before malignant conversion. Kim et al. (2003) found 7 KRAS missense
mutations in 66 gastric cancers and 16 gastric cancer cell lines. No
BRAF mutations were found.

Oliveira et al. (2004) investigated KRAS in 158 hereditary nonpolyposis
colorectal cancer (HNPCC2; 609310) tumors from patients with germline
MLH1 (120436), MSH2 (609309) or MSH6 (600678) mutations, 166
microsatellite-unstable (MSI-H), and 688 microsatellite-stable (MSS)
sporadic carcinomas. All tumors were characterized for MSI and 81 of 166
sporadic MSI-H colorectal cancers were analyzed for MLH1 promoter
hypermethylation. KRAS mutations were observed in 40% of HNPCC tumors,
and the mutation frequency varied upon the mismatch repair gene
affected: 48% (29/61) in MSH2, 32% (29/91) in MLH1, and 83% (5/6) in
MSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC,
MSS, and MSI-H colorectal cancers (P = 0.002), and MSI-H with MLH1
hypermethylation (P = 0.005). Furthermore, HNPCC colorectal cancers had
more G13D (190070.0003) mutations than MSS (P less than 0.0001), MSI-H
(P = 0.02) or MSI-H tumors with MLH1 hypermethylation (P = 0.03). HNPCC
colorectal and sporadic MSI-H tumors without MLH1 hypermethylation
shared similar KRAS mutation frequency, in particular G13D. The authors
concluded that depending on the genetic/epigenetic mechanism leading to
MSI-H, the outcome in terms of oncogenic activation may be different,
reinforcing the idea that HNPCC, sporadic MSI-H (depending on the MLH1
status) and MSS colorectal cancers may target distinct kinases within
the RAS/RAF/MAPK pathway.

Sommerer et al. (2005) analyzed the KRAS gene in 30 seminomas and 32
nonseminomatous GCTs (see 273300) with a mixture of embryonal carcinoma,
yolk sac tumor, choriocarcinoma, and mature teratoma. KRAS mutations,
all involving codon 12, were identified in 2 (7%) of 30 seminomas and 3
(9%) of 32 nonseminomas.

Groesser et al. (2012) identified somatic mutations in the KRAS gene
(G12D, 190070.0005 and G12V, 190070.0006) in 3 (5%) of 65 nevus
sebaceous tumors (see 162900). The G12D mutation was also found in
somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims
syndrome (163200). The authors postulated that the mosaic mutation
likely extends to extracutaneous tissues in the latter disorder, which
could explain the phenotypic pleiotropy.

Vermeulen et al. (2013) quantified the competitive advantage in tumor
development of Apc (611731) loss, Kras activation, and p53 (191170)
mutations in the mouse intestine. Their findings indicated that the fate
conferred by these mutations is not deterministic, and many mutated stem
cells are replaced by wildtype stem cells after biased but still
stochastic events. Furthermore, Vermeulen et al. (2013) found that p53
mutations display a condition-dependent advantage, and especially in
colitis-affected intestines, clones harboring mutations in this gene
were favored. Vermeulen et al. (2013) concluded that their work
confirmed the notion that the tissue architecture of the intestine
suppresses the accumulation of mutated lineages.

- Hematologic Malignancies

The myelodysplastic syndrome is a preleukemic hematologic disorder
characterized by low blood counts, bone marrow cells of abnormal
appearance, and progression to acute leukemia in as many as 30% of
patients. Liu et al. (1987) identified a transforming allele in the KRAS
gene in 2 of 4 patients with preleukemia and in 1 who progressed to
acute leukemia from myelodysplastic syndrome. In 1 preleukemic patient,
they detected a novel mutation in codon 13 of KRAS in bone marrow cells
harvested 1.5 years before the acute leukemia developed. The findings
provided evidence that RAS mutations may be involved in the early stages
of human leukemia.

In the bone marrow of a 4-year-old child with acute myeloid leukemia
(AML; 601626), Bollag et al. (1996) identified an in-frame 3-bp
insertion in the KRAS gene (190070.0008).

Bezieau et al. (2001) used ARMS (allele-specific amplification method)
to evaluate the incidence of NRAS- and KRAS2-activating mutations in
patients with multiple myeloma (254500) and related disorders. Mutations
were more frequent in KRAS2 than in NRAS. The authors concluded that
early mutations in these 2 oncogenes may play a major role in the
oncogenesis of multiple myeloma and primary plasma cell leukemia.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. The Cancer Genome Atlas Research Network (2013) identified
recurrent mutations in the NRAS (164790) or KRAS genes in 23/200 (12%)
samples.

- Cardiofaciocutaneous Syndrome, Noonan Syndrome 3, and Costello
Syndrome

Cardiofaciocutaneous (CFC) syndrome (see 115150) is characterized by
distinctive facial appearance, heart defects, and mental retardation.
CFC shows phenotypic overlap with Noonan syndrome (see 163950) and
Costello syndrome (218040). Approximately 40% of individuals with
clinically diagnosed Noonan syndrome have gain-of-function mutations in
protein-tyrosine phosphatase SHP2 (PTPN11; 176876). Aoki et al. (2005)
identified mutations in the HRAS gene in 12 of 13 individuals with
Costello syndrome, suggesting that the activation of the RAS-MAPK
pathway is the common underlying mechanism of Noonan syndrome, Costello
syndrome, and possibly CFC syndrome. In 2 of 43 unrelated individuals
with CFC syndrome (CFC2; 615278), Niihori et al. (2006) identified 2
different heterozygous KRAS mutations, G60R (190070.0009) and D153V
(190070.0010). Neither mutation had been previously identified in
individuals with cancer. In the same study, Niihori et al. (2006) found
8 different mutations in the BRAF gene (164757), an isoform in the RAF
protooncogene family, in 16 of 40 individuals with CFC syndrome.

Schubbert et al. (2006) identified 3 de novo germline KRAS mutations
(190070.0010-190070.0012) in 5 individuals with Noonan syndrome 3 (NS3;
609942).

In 2 individuals exhibiting a severe Noonan syndrome-3 phenotype with
features overlapping those of CFC and Costello syndromes, Carta et al.
(2006) identified 2 different heterozygous KRAS mutations (190070.0014
and 190070.0015). Both mutations were de novo and affected exon 6, which
encodes the C-terminal portion of KRAS isoform B but does not contribute
to KRAS isoform A. Structural analysis indicated that both substitutions
perturb the conformation of the guanine ring-binding pocket of the
protein, predicting an increase in the guanine diphosphate/guanine
triphosphate (GTP) dissociation rate that would favor GTP binding to the
KRASB isoform and bypass the requirement for a guanine nucleotide
exchange factor.

Zenker et al. (2007) identified 11 different germline mutations in the
KRAS gene, including 8 novel mutations, in a total of 12 patients with a
clinical diagnosis of CFC (2), Noonan syndrome-3 (7), CFC/Noonan
syndrome overlap (1), or Costello syndrome (2). All patients showed mild
to moderate mental retardation. The 2 unrelated infants with Costello
syndrome had 2 different heterozygous mutations
(190070.0017-190070.0018). Both patients had coarse facies, loose and
redundant skin with deep palmar creases, heart defects, failure to
thrive, and moderate mental retardation. Zenker et al. (2007) noted that
these patients may later develop features of CFC syndrome, but
emphasized that the findings underscored the central role of Ras in the
pathogenesis of these diverse but phenotypically related disorders.

In a 20-year-old woman with clinical features typical of Costello
syndrome and additional findings seen in Noonan syndrome, who was
negative for mutations in the PTPN11 and HRAS genes, Bertola et al.
(2007) identified a mutation in the KRAS gene (K5E; 190070.0019). The
authors noted that this mutation was in the same codon as that of 1 of
the patients reported by Zenker et al. (2007) (K5N; 190070.0017).

Schulz et al. (2008) identified mutations in the KRAS gene in 3 (5.9%)
of 51 CFC patients.

- Development of Resistance to Chemotherapeutic Agents

Misale et al. (2012) showed that molecular alterations (in most
instances point mutations) of KRAS are causally associated with the
onset of acquired resistance to anti-EGFR (131550) treatment in
colorectal cancers. Expression of mutant KRAS under the control of its
endogenous gene promoter was sufficient to confer cetuximab resistance,
but resistant cells remained sensitive to combinatorial inhibition of
EGFR and mitogen-activated protein kinase kinase (MEK). Analysis of
metastases from patients who developed resistance to cetuximab or
panitumumab showed the emergence of KRAS amplification in one sample and
acquisition of secondary KRAS mutations in 60% (6 out of 10) of the
cases. KRAS mutant alleles were detectable in the blood of
cetuximab-treated patients as early as 10 months before radiographic
documentation of disease progression. Misale et al. (2012) concluded
that their results identified KRAS mutations as frequent drivers of
acquired resistance to cetuximab in colorectal cancers, indicated that
the emergence of KRAS mutant clones can be detected noninvasively months
before radiographic progression, and suggested early initiation of a MEK
inhibitor as a rational strategy for delaying or reversing drug
resistance.

Diaz et al. (2012) determined whether mutant KRAS DNA could be detected
in the circulation of 28 patients receiving monotherapy with
panitumumab, a therapeutic anti-EGFR antibody. They found that 9 out of
24 (38%) patients whose tumors were initially KRAS wildtype developed
detectable mutations in KRAS in their sera, 3 of which developed
multiple different KRAS mutations. The appearance of these mutations was
very consistent, generally occurring between 5 and 6 months following
treatment. Mathematical modeling indicated that the mutations were
present in expanded subclones before the initiation of panitumumab
treatment. Diaz et al. (2012) suggested that the emergence of KRAS
mutations is a mediator of acquired resistance to EGFR blockade and that
these mutations can be detected in a noninvasive manner. The results
also explained why solid tumors develop resistance to targeted therapies
in a highly reproducible fashion.

GENOTYPE/PHENOTYPE CORRELATIONS

Andreyev et al. (1997) used PCR amplification and DNA sequencing to
investigate KRAS exon 1 mutations (codons 12 and 13) in histologic
sections of colorectal adenocarcinomas. They examined samples from 98
patients with Dukes stage A or B fully resected colorectal cancers.
Fourteen of these patients had subsequently relapsed. The presence of a
KRAS mutation was not associated with tumor stage or histologic grade;
neither was there any association with those patients who relapsed. The
authors concluded that detection of KRAS mutation in early colorectal
adenocarcinomas was of no prognostic value.

Porta et al. (1999) found that serum concentrations of organochlorine
compounds were significantly higher in patients with exocrine pancreatic
cancer with a codon 12 KRAS2 mutation compared to cases without a
mutation, with an odds ratio of 8.7 for one organochlorine and 5.3 for
another organochlorine. These estimates held after adjusting for total
lipids, other covariates, and total polychlorinated biphenyls (PCBs). A
specific association was observed between the G12V (190070.0006)
mutation and both organochlorine concentrations, with an odds ratio of
15.9 and 24.1 for each of the compounds. A similar pattern was shown for
the major diorthochlorinated PCBs.

Vasko et al. (2003) performed a pooled analysis of 269 mutations in
HRAS, KRAS, and NRAS garnered from 39 previous studies of thyroid
tumors. Mutations in codon 61 of NRAS were significantly more frequent
in follicular tumors (19%) than in papillary tumors (188550) (5%) and
significantly more frequent in malignant (25%) than in benign (14%)
tumors. HRAS mutations in codons 12/13 were found in 2 to 3% of all
types of tumors, but HRAS mutations in codon 61 were observed in only
1.4% of tumors, and almost all of them were malignant. KRAS mutations in
exon 1 were found more often in papillary than follicular cancers (2.7%
vs 1.6%) and were sometimes correlated with special epidemiologic
circumstances. The second part of the study by Vasko et al. (2003)
involved analysis of 80 follicular tumors from patients living in
Marseille (France) and Kiev (Ukraine). HRAS mutations in codons 12/13
were found in 12.5% of common adenomas and in 1 follicular carcinoma
(2.9%). Mutations in codon 61 of NRAS occurred in 23.3% and 17.6% of
atypical adenomas and follicular carcinomas, respectively.

POPULATION GENETICS

Although several studies confirmed that approximately 40% of primary
colorectal adenocarcinomas in humans contain a mutated form of the KRAS2
gene, the patterns of mutation at codons 12, 13, and 61 are not the same
in different populations. Hayashi et al. (1996) used the MASA method to
analyze the frequency and type of point mutations in these 3 codons in
319 colorectal cancer tissues collected from patients in Japan. They
then compared these results with those from other sources to examine
whether different geographic locations and environmental influences
might impose distinct patterns on the spectrum of KRAS mutations.
Comparing findings in the U.S., France, and Yugoslavia with those in
Japan, a number of significant differences were found. A possible
explanation put forth by Hayashi et al. (1996) was that an environmental
carcinogen prevailing in a geographic region combines with the
susceptibility of a particular tissue to dictate which type of DNA
lesion will predominate. The predominance of G-to-A mutations among
American and Japanese colorectal cancer patients could be attributable
to alkylating agents or to the absence of direct interaction with any
carcinogens. The prevalence of G-to-T mutations among Yugoslav and
French patients might be ascribed to polycyclic aromatic hydrocarbons
and heterocyclic amines.

ANIMAL MODEL

Muller et al. (1983) found transcription of KRAS and the McDonough
strain of feline sarcoma virus (FMS) gene (see 164770) during mouse
development. Furthermore, the differences in transcription in different
tissues suggested a specific role for each: FMS was expressed in
extraembryonic structures or in transport in these tissues, whereas KRAS
was expressed ubiquitously.

Holland et al. (2000) transferred, in a tissue-specific manner, genes
encoding activated forms of Ras and Akt (164730) to astrocytes and
neural progenitors in mice. Although neither activated Ras nor Akt alone
was sufficient to induce glioblastoma multiforme (GBM; 137800)
formation, the combination of activated Ras and Akt induced high-grade
gliomas with the histologic features of human GBMs. These tumors
appeared to arise after gene transfer to neural progenitors, but not
after transfer to differentiated astrocytes. Increased activity of RAS
is found in many human GBMs, and Holland et al. (2000) demonstrated that
AKT activity is increased in most of these tumors, implying that
combined activation of these 2 pathways accurately models the biology of
this disease.

Johnson et al. (2001) used a variation of 'hit-and-run' gene targeting
to create mouse strains carrying oncogenic alleles of Kras capable of
activation only on a spontaneous recombination event in the whole
animal. They demonstrated that mice carrying these mutations were highly
predisposed to a range of tumor types, predominantly early-onset lung
cancer. This model was further characterized by examining the effects of
germline mutations in the p53 gene (191170), which is known to be
mutated along with KRAS in human tumors. Johnson et al. (2001) concluded
that their approach had several advantages over traditional transgenic
strategies, including that it more closely recapitulates spontaneous
oncogene activation as seen in human cancers.

Zhang et al. (2001) presented evidence of a tumor suppressor role of
wildtype KRAS2 in lung tumorigenesis. They found that heterozygous
Kras2-deficient mice were highly susceptible to the chemical induction
of lung tumors compared to wildtype mice. Activating Kras2 mutations
were detected in all chemically induced lung tumors obtained from both
wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype
Kras2 inhibited colony formation and tumor development by transformed
NIH/3T3 cells. Allelic loss of wildtype Kras2 was found in 67 to 100% of
chemically induced mouse lung adenocarcinomas that harbored a mutant
Kras2 allele. These and other data strongly suggested that wildtype
Kras2 has tumor suppressor activity and is frequently lost during lung
tumor progression. Pfeifer (2001) commented on these findings as
representing 'a new verdict for an old convict.' He quoted evidence that
the HRAS1 gene may also function as a tumor suppressor. Pfeifer (2001)
noted an interesting parallel to the p53 tumor suppressor, which was
initially described as an oncogene, carrying point mutations in tumors.
Later it was discovered that it is, in fact, the wildtype copy of the
gene that functions as a tumor suppressor gene and is capable of
reducing cell proliferation.

Costa et al. (2002) crossed Nf1 (613113) heterozygote mice with mice
heterozygous for a null mutation in the Kras gene. Double heterozygotes
with decreased Ras function had improved learning relative to Nf1
heterozygote mice. Costa et al. (2002) also showed that the Nf1 +/- mice
have increased GABA-mediated inhibition and specific deficits in
long-term potentiation, both of which can be reversed by decreasing Ras
function. Costa et al. (2002) concluded that learning deficits
associated with Nf1 may be caused by excessive Ras activity, which leads
to impairments in long-term potentiation caused by increased
GABA-mediated inhibition.

An S17N substitution in any of the RAS proteins produces
dominant-inhibitory proteins with higher affinities for exchange factors
than normal RAS. These mutants cannot interact with downstream effectors
and therefore form unproductive complexes, preventing activation of
endogenous RAS. Using experiments in COS-7 cells, mouse fibroblasts, and
canine kidney cells, Matallanas et al. (2003) found that the Hras, Kras,
and Nras S17N mutants exhibited distinct inhibitory effects that
appeared to be due largely to their specific membrane localizations. The
authors demonstrated that Hras is present in caveolae, lipid rafts, and
bulk disordered membranes, whereas Kras and Nras are present primarily
in disordered membranes and lipid rafts, respectively. Thus, the Hras
S17N mutant inhibited activation of all 3 wildtype RAS isoforms, the
Kras S17N mutant inhibited wildtype Kras and the portion of Hras in
disordered membranes, and the Nras S17N mutant inhibited wildtype Nras
and the portion of Hras in lipid rafts.

By delivering a recombinant adenoviral vector expressing Cre recombinase
to the bursal cavity that encloses the ovary, Dinulescu et al. (2005)
expressed an oncogenic Kras allele within the ovarian surface epithelium
and observed benign epithelial lesions with a typical endometrioid
glandular morphology that did not progress to ovarian carcinoma
(167000); 7 of 15 mice (47%) also developed peritoneal endometriosis
(131200). When the Kras mutation was combined with conditional deletion
of Pten (601728), all mice developed invasive endometrioid ovarian
adenocarcinomas. Dinulescu et al. (2005) stated that these were the
first mouse models of endometriosis and endometrioid adenocarcinoma of
the ovary.

Collado et al. (2005) used a mouse model for cancer initiation in
humans: the animals had a conditional oncogenic K-rasV12 (190070.0006)
allele that is activated only by the enzyme Cre recombinase, causing
them to develop multiple lung adenomas (premalignant tumors) and a few
lung adenocarcinomas (malignant tumors). Senescence markers previously
identified in cultured cells were used to detect oncogene-induced
senescence in lung sections from control mice (expressing Cre) and from
K-rasV12-expressing mice (expressing Cre and activated K-rasV12).
Collado et al. (2005) analyzed p16(INK4a) (600160), an effector of in
vitro oncogene-induced senescence, and de novo markers that were
identified by using DNA microarray analysis of in vitro oncogene-induced
senescence. These de novo markers are p15(INK4b), also known as CDKN2B
(600431), DEC1 (BHLHB2; 604256), and DCR2 (TNFRSF10D; 603614). Staining
with antibodies against p16(INK4a), p15(INK4b), DEC1, and DCR2 revealed
abundant positive cells in adenomas, whereas adenocarcinomas were
essentially negative. By contrast, the proliferation marker Ki-67
revealed a weak proliferative index in adenomas compared with
adenocarcinomas. Collado et al. (2005) concluded that oncogene-induced
senescence may help to restrict tumor progression. They concluded that a
substantial number of cells in premalignant tumors undergo
oncogene-induced senescence, but that cells in malignant tumors are
unable to do this owing to the loss of oncogene-induced senescence
effectors such as p16(INK4a) or p53.

Using an Hras (190020) knockin mouse model, To et al. (2008)
demonstrated that specificity for Kras mutations in lung and Hras
mutations in skin tumors is determined by local regulatory elements in
the target Ras genes. Although the Kras 4A isoform is dispensable for
mouse development, it is the most important isoform for lung
carcinogenesis in vivo and for the inhibitory effect of wildtype Kras on
the mutant allele. Kras 4A expression is detected in a subpopulation of
normal lung epithelial cells, but at very low levels in lung tumors,
suggesting that it may not be required for tumor progression. The 2 Kras
isoforms undergo different posttranslational modifications. To et al.
(2008) concluded that their findings may have implications for the
design of therapeutic strategies for inhibiting oncogenic Kras activity
in human cancers.

Junttila et al. (2010) modeled the probable therapeutic impact of p53
(191170) restoration in a spontaneously evolving mouse model of nonsmall
cell lung cancer (NSCLC) initiated by sporadic oncogenic activation of
endogenous KRAS developed by Jackson et al. (2001). Surprisingly, p53
restoration failed to induce significant regression of established
tumors, although it did result in a significant decrease in the relative
proportion of high-grade tumors. This was due to selective activation of
p53 only in the more aggressive tumor cells within each tumor. Such
selective activation of p53 correlates with marked upregulation in Ras
signal intensity and induction of the oncogenic signaling sensor
p19(ARF) (600160). Junttila et al. (2010) concluded that p53-mediated
tumor suppression is triggered only when oncogenic Ras signal flux
exceeds a critical threshold. Importantly, the failure of low-level
oncogenic Kras to engage p53 reveals inherent limits in the capacity of
p53 to restrain early tumor evolution and in the efficacy of therapeutic
p53 restoration to eradicate cancers.

*FIELD* AV
.0001
LUNG CANCER, SOMATIC
KRAS, GLY12CYS

In a cell line of human lung cancer (211980), Nakano et al. (1984)
identified a 34G-T transversion in exon 1 of the KRAS2 gene, resulting
in a gly12-to-cys (G12C) substitution. Studies of the mutant protein
showed that it had transforming abilities consistent with activation of
the gene.

In a study of 106 prospectively enrolled patients with primary
adenocarcinoma of the lung, Ahrendt et al. (2001) found that 92 (87%)
were smokers. KRAS2 mutations were detected in 40 of 106 tumors (38%)
and were significantly more common in smokers compared with nonsmokers
(43% vs 0%; P = 0.001). Thirty-nine of the 40 tumors with KRAS2
mutations had 1 of 4 changes in codon 12, the most common being G12C,
which was present in 25 tumors.

.0002
LUNG CANCER, SQUAMOUS CELL, SOMATIC
BLADDER CANCER, SOMATIC, INCLUDED
KRAS, GLY12ARG

In a squamous cell lung carcinoma (211980) from a 66-year-old man,
Santos et al. (1984) identified a G-to-C transversion in exon 1 of the
KRAS2 gene, resulting in a gly12-to-arg (G12R) substitution. The
mutation was not identified in the patient's normal bronchial and
pulmonary parenchymal tissues or blood lymphocytes. This mutation had
previously been identified in a bladder cancer (109800) and a lung
cancer.

.0003
BREAST ADENOCARCINOMA, SOMATIC
KRAS, GLY13ASP

In a cell line from a human breast adenocarcinoma (114480), Kozma et al.
(1987) identified a heterozygous G-to-A transition in exon 1 of the
KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and
activation of the protein.

.0004
BLADDER CANCER, TRANSITIONAL CELL, SOMATIC
KRAS, ALA59THR

In a human transitional cell bladder carcinoma cell line (109800),
Grimmond et al. (1992) identified a heterozygous G-to-A transition in
the KRAS2 gene, resulting in an ala59-to-thr (A59T) substitution. The
mutation was present in paraffin-embedded tissue from the primary tumor
of the patient.

.0005
PANCREATIC CARCINOMA, SOMATIC
GASTRIC CANCER, SOMATIC, INCLUDED;;
EPIDERMAL NEVUS, SOMATIC, INCLUDED;;
NEVUS SEBACEOUS, SOMATIC, INCLUDED;;
SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC, INCLUDED
KRAS, GLY12ASP

Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53
pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations
were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006),
respectively.

Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of
140 cases of gastric cancer (137215); 2 cases had G12D.

Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in
a female infant with an epidermal nevus (162900) who developed a
uterovaginal rhabdomyosarcoma at age 6 months. There was also an
incidental finding of micropolycystic kidneys without impaired renal
function. Both the epidermal nevus and the rhabdomyosarcoma carried the
G12D mutation, which was not found in normal dermal tissue, bone, cheek
swap, or lymphocytes. No renal tissue was available for study. The
phenotype was consistent with broad activation of the KRAS pathway.

Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65
(3%) nevus sebaceous tumors (see 162900). One of the tumors also carried
a somatic mutation in the HRAS gene (G13R; 190020.0017). The KRAS G12D
mutation was also found in somatic mosaic state in a patient with
Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally
reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012)
postulated that the mosaic mutation likely extends to extracutaneous
tissues in that disorder, which could explain the phenotypic pleiotropy.

Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72
keratinocytic epidermal nevi.

.0006
PANCREATIC CARCINOMA, SOMATIC
NEVUS SEBACEOUS, SOMATIC, INCLUDED
KRAS, GLY12VAL

See 190070.0005 and Motojima et al. (1993).

Groesser et al. (2012) identified a somatic G12V mutation in 1 (2%) of
65 nevus sebaceous tumors (see 162900). The tumor also carried a somatic
mutation in the HRAS gene (G13R; 190020.0017).

.0007
GASTRIC CANCER, SOMATIC
KRAS, GLY12SER

Lee et al. (1995) found mutations in codon 12 of the KRAS2 gene in 9 of
140 cases of gastric cancer (137215); 7 cases had a G-to-A transition,
resulting in a gly12-to-ser (G12S) substitution.

.0008
LEUKEMIA, ACUTE MYELOGENOUS
KRAS, 3-BP INS, GLY11INS

In the bone marrow of a 4-year-old child with acute myeloid leukemia
(AML; 601626), Bollag et al. (1996) identified an in-frame 3-bp
insertion in exon 1 of the KRAS2 gene, resulting in an insertion of
gly11. Expression of the mutant protein in NIH 3T3 cells caused cellular
transformation, and expression in COS cells activated the
RAS-mitogen-activated protein kinase signaling pathway. RAS-GTP levels
measured in COS cells established that this novel mutant accumulates up
to 90% in the GTP state, considerably higher than a residue 12 mutant.
This mutation was the first dominant RAS mutation found in human cancer
that did not involve residues 12, 13, or 61.

.0009
CARDIOFACIOCUTANEOUS SYNDROME 2
KRAS, GLY60ARG

In an individual with CFC syndrome (CFC2; 615278), Niihori et al. (2006)
identified a heterozygous 178G-C transversion in exon 2 of the KRAS2
gene, predicting a gly60-to-arg (G60R) amino acid change.

.0010
CARDIOFACIOCUTANEOUS SYNDROME 2
NOONAN SYNDROME 3, INCLUDED
KRAS, ASP153VAL

In 2 unrelated individuals with CFC syndrome (CFC2; 615278), Niihori et
al. (2006) identified a heterozygous 458A-T transversion in exon 4b of
the KRAS2 gene, predicting an asp153-to-val (D153V) amino acid change.
The D153V mutation was identified in DNA extracted from both blood and
buccal cells of 1 of the individuals. This heterozygous mutation and
G60R (190070.0009) were not found in 100 control chromosomes and were
not found in any parent. The results suggested that these germline
mutations occurred de novo.

Schubbert et al. (2006) found the D153V mutation in a patient who had
been diagnosed with Noonan syndrome-3 (609942). The 18-year-old male had
hypertrophic cardiomyopathy, dysplastic mitral valve with prolapse,
Noonan-like features, short stature, mild pectus carinatum, unilateral
cryptorchidism, mild developmental delay, and grand mal seizures.

.0011
NOONAN SYNDROME 3
KRAS, THR58ILE

In a 3-month-old female with Noonan syndrome-3 (609942), Schubbert et
al. (2006) identified a heterozygous 173C-T transition in the KRAS2
gene, resulting in a thr58-to-ile (T58I) substitution. The child had a
severe clinical phenotype and presented with a myeloproliferative
disorder of the juvenile myelomonocytic leukemia (JMML; 607785) type.
The mutation was present in the patient's buccal cells but was absent in
parental DNA. Clinical features included atrial septal defect,
ventricular septal defect, valvular pulmonary stenosis, dysmorphic
facial features, short stature, webbed neck, severe developmental delay,
macrocephaly, and sagittal suture synostosis.

Kratz et al. (2009) identified a de novo heterozygous T58I mutation in a
patient with Noonan syndrome who also had craniosynostosis, suggesting a
genotype/phenotype correlation. The findings indicated that dysregulated
RAS signaling may lead to abnormal growth or premature calvarian
closure.

.0012
NOONAN SYNDROME 3
KRAS, VAL14ILE

In 3 of 124 unrelated individuals with Noonan syndrome-3 (609942)
without mutations in PTPN11 (176876), Schubbert et al. (2006) identified
a heterozygous 40G-A transition in the KRAS2 gene, resulting in a
val14-to-ile (V14I) substitution. Each individual showed a mild clinical
phenotype, and none had a history of myeloproliferative disorder or
cancer.

.0013
CARDIOFACIOCUTANEOUS SYNDROME 2
KRAS, PRO34ARG

In a 13-year-old female with the diagnosis of cardiofaciocutaneous
syndrome (CFC2; 615278), Schubbert et al. (2006) found a heterozygous
pro34-to-arg (P34R) mutation in the KRAS2 gene. The patient had pulmonic
stenosis, left ventricular hypertrophy, Noonan-like facial features,
short stature, short neck, broad thorax, lymphedema, chylothorax, left
ptosis, severe developmental delay, and agenesis of the corpus callosum.

.0014
NOONAN SYNDROME 3
KRAS, VAL152GLY

In a 1-year-old girl with the diagnosis of Noonan syndrome-3 (609942),
Carta et al. (2006) identified a 455T-G transversion in the KRAS2 gene,
resulting in a val152-to-gly (V152G) substitution. The patient had
macrocephaly with high and broad forehead, curly and sparse hair,
hypertelorism, strabismus, epicanthic folds, downslanting palpebral
fissures, hypoplastic nasal bridge with bulbous tip of the nose, high
palate and macroglossia, low-set and posteriorly rotated ears, short
neck with redundant skin, wide-set nipples, and umbilical hernia. She
had been born at 32 weeks' gestation by cesarean section after a
pregnancy complicated by a cystic hygroma detected at 12 weeks and
polyhydramnios at 30 weeks. At birth she showed edema of the lower
limbs. The phenotype showed features overlapping Costello syndrome
(218040) (polyhydramnios, neonatal macrosomia, and macrocephaly, loose
skin, and severe failure to thrive) and, to a lesser extent, CFC
syndrome (115150) (macrocephaly and sparse hair).

.0015
NOONAN SYNDROME 3
KRAS, ASP153VAL

In a 14-year-old girl with Noonan syndrome-3 (609942) and some features
of CFC syndrome (115150), Carta et al. (2006) identified a 458A-T
transversion in the KRAS2 gene, resulting in an asp153-to-val (D153V)
substitution. The girl had short stature and growth retardation and
delayed bone age, cardiac defects (moderate ventricular hypertrophy,
mild pulmonic stenosis, and atrial septal defect), dysmorphic features
(hypertelorism, downslanting palpebral fissures, strabismus, low-set and
thick ears, relative macrocephaly with high forehead, and a depressed
nasal bridge), short and mildly webbed neck, wide-set nipples, and
developmental delay. There was hyperpigmentation of the skin and a large
cafe-au-lait spot on the face. Gestation was complicated by
polyhydramnios.

.0016
PILOCYTIC ASTROCYTOMA, SOMATIC
KRAS, GLY13ARG

In 1 of 21 sporadic pilocytic astrocytoma (PA) (see 137800) samples,
Sharma et al. (2005) identified a G-to-C transversion in the KRAS2 gene,
resulting in a gly13-to-arg (G13R) substitution. The tumor arose in the
cortex of an 11-year-old boy; the mutation was not identified in the
germline of the patient. Immunohistochemical studies showed increased
phospho-AKT (see 164730) activity compared to controls in all 21 PA
samples, indicating increased activation of the Ras pathway. No
mutations in the KRAS gene were observed in the other tumors, and none
of the 21 tumors showed mutations in the HRAS (190020) or NRAS (164790)
genes. Of note, the G13R substitution occurs in the same codon as
another KRAS mutation (G13D; 190070.0003) identified in a breast
carcinoma cell line.

.0017
CARDIOFACIOCUTANEOUS SYNDROME 2
KRAS, LYS5ASN

In a 7.5-month-old male infant with a clinical diagnosis of Costello
syndrome (218040), Zenker et al. (2007) identified a heterozygous 15A-T
transversion in exon 1 of the KRAS2 gene, resulting in a lys5-to-asn
(K5N) substitution. The patient had hypertelorism, downslanting
palpebral fissures, coarse facies, pectus carinatum, sparse hair,
redundant skin, and moderate mental retardation. Zenker et al. (2007)
noted that the patient may later develop features of CFC (CFC2; 615278),
which is commonly associated with KRAS mutations, but emphasized that
the findings underscored the central role of Ras in the pathogenesis of
these phenotypically related disorders.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome
should be used only to refer to patients with mutations in the HRAS gene
(190020).

.0018
CARDIOFACIOCUTANEOUS SYNDROME 2
KRAS, PHE156LEU

In a male infant with a clinical diagnosis of Costello syndrome (218040)
who died suddenly at age 14 months, Zenker et al. (2007) identified a
heterozygous 468C-G transversion in the KRAS2 gene, resulting in a
phe156-to-leu (F156L) substitution. The patient had coarse facies,
cardiac defects, sparse hair, loose and redundant skin, developmental
delay, and moderate mental retardation. Zenker et al. (2007) noted that
the patient may later develop features of CFC (CFC2; 615278), which is
commonly associated with KRAS mutations, but emphasized that the
findings underscored the central role of Ras in the pathogenesis of
these phenotypically related disorders.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome
should be used only to refer to patients with mutations in the HRAS gene
(190020).

.0019
NOONAN SYNDROME 3
KRAS, LYS5GLU

In a 20-year-old woman with clinical features typical of Costello
syndrome (218040) and additional findings seen in Noonan syndrome
(609942), Bertola et al. (2007) identified a 194A-G transition in exon 2
of the KRAS gene, resulting in a lys5-to-glu (K5E) substitution. The
mutation was not found in her unaffected mother or brother or in 100
controls.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome
should be used only to refer to patients with mutations in the HRAS gene
(190020).

Bertola et al. (2012) reported a patient with a germline K5E mutation
and dysmorphic features who developed multiple diffuse schwannomas.

.0020
NOONAN SYNDROME 3
KRAS, GLY60SER

In a patient with Noonan syndrome-3 (609942) and craniosynostosis, Kratz
et al. (2009) identified a de novo heterozygous 178G-A transition in the
KRAS gene, resulting in a gly60-to-ser (G60S) substitution. The findings
indicated that dysregulated RAS signaling may lead to abnormal growth or
premature calvarian closure.

A mutation in this same codon (G60R; 190070.0009) has been found in a
patient with cardiofaciocutaneous syndrome (115150).

.0021
CARDIOFACIOCUTANEOUS SYNDROME 2
KRAS, TYR71HIS

In a mother and son with variable features of cardiofaciocutaneous
syndrome (CFC2; 615278), Stark et al. (2012) identified a heterozygous
211T-C transition in exon 3 of the KRAS gene, resulting in a
tyr71-to-his (Y71H) substitution in a highly conserved residue close to
a region that is important for effector and regulator binding. The
mutation was not found in 500 control individuals and was shown by in
vitro studies to increase effector affinity. The son had delayed
psychomotor development and a distinctive appearance, including curly
hair, absent eyebrows, and broad forehead. Echocardiogram was normal at
age 3 years. His mother had a similar physical appearance and also had
high-arched palate, myopia, and mitral valve prolapse. She had attended
a school for children with special needs. Both patients showed signs of
a peripheral sensorimotor axonal neuropathy, more severe in the mother,
who developed Charcot arthropathy of the feet. PMP22 (601097) testing in
the mother was negative, but an additional cause of the neuropathy could
not be excluded. The authors stated that this was the first documented
vertically transmitted KRAS mutation.

.0022
CARDIOFACIOCUTANEOUS SYNDROME 2
KRAS, LYS147GLU

In a girl with variable features of CFC (CFC2; 615278), Stark et al.
(2012) identified a de novo heterozygous 439A-G transition in exon 4 of
the KRAS gene, resulting in a lys147-to-glu (K147E) substitution in a
highly conserved residue close to known mutations. Lys147 is part of a
motif involved in the binding network for guanine nucleotides, which
determine the activation state of RAS proteins. In vitro studies
demonstrated that the K147E mutant protein predominates in the active
GTP-bound form, probably due to facilitated uncatalyzed GDP/GTP
exchange. The patient was 1 of a female dizygotic twin pair; the other
twin was unaffected. The patient had a high birth weight, macrocephaly,
and abnormal craniofacial features, including proptosis, hypertelorism,
downslanting palpebral fissures, low-set ears, and short neck,
suggestive of Noonan syndrome. Reexamination at age 3.5 years showed
coarser facial features more consistent with CFC. She also had
hypertrophy of the interventricular myocardial septum, myocardial
hypertrophy, and pulmonic stenosis. She had mildly delayed development.

*FIELD* SA
Capon et al. (1983); Der and Cooper (1983); Sakaguchi et al. (1984);
Shimizu et al. (1983)
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*FIELD* CN
Ada Hamosh - updated: 12/06/2013
Ada Hamosh - updated: 7/9/2013
Ada Hamosh - updated: 7/8/2013
Cassandra L. Kniffin - updated: 1/30/2013
Cassandra L. Kniffin - updated: 7/25/2012
Ada Hamosh - updated: 7/17/2012
Cassandra L. Kniffin - updated: 6/28/2012
Marla J. F. O'Neill - updated: 11/29/2011
Cassandra L. Kniffin - updated: 2/21/2011
Ada Hamosh - updated: 2/3/2011
Ada Hamosh - updated: 8/17/2010
Ada Hamosh - updated: 3/9/2010
Ada Hamosh - updated: 12/29/2009
Cassandra L. Kniffin - updated: 10/27/2009
Ada Hamosh - updated: 10/13/2009
Marla J. F. O'Neill - updated: 6/1/2009
Cassandra L. Kniffin - updated: 3/3/2009
Ada Hamosh - updated: 1/20/2009
Ada Hamosh - updated: 7/29/2008
Cassandra L. Kniffin - updated: 3/17/2008
Ada Hamosh - updated: 11/12/2007
George E. Tiller - updated: 4/5/2007
Cassandra L. Kniffin - reorganized: 3/8/2007
Cassandra L. Kniffin - updated: 3/2/2007
Cassandra L. Kniffin - updated: 2/15/2007
Ada Hamosh - updated: 2/8/2007
Ada Hamosh - updated: 11/28/2006
Victor A. McKusick - updated: 6/13/2006
Patricia A. Hartz - updated: 4/10/2006
Patricia A. Hartz - updated: 3/28/2006
Victor A. McKusick - updated: 2/24/2006
Ada Hamosh - updated: 9/7/2005
Stylianos E. Antonarakis - updated: 3/28/2005
Marla J. F. O'Neill - updated: 3/22/2005
Victor A. McKusick - updated: 12/16/2003
John A. Phillips, III - updated: 9/2/2003
Ada Hamosh - updated: 9/17/2002
Victor A. McKusick - updated: 8/15/2002
Victor A. McKusick - updated: 12/13/2001
Victor A. McKusick - updated: 9/26/2001
Victor A. McKusick - updated: 9/4/2001
Victor A. McKusick - updated: 8/24/2001
Ada Hamosh - updated: 4/23/2001
Ada Hamosh - updated: 4/28/2000
Ada Hamosh - updated: 2/11/2000
Paul Brennan - updated: 7/31/1998
Victor A. McKusick - updated: 3/27/1998
Paul Brennan - updated: 11/14/1997
Victor A. McKusick - edited: 3/3/1997
Mark H. Paalman - edited: 1/10/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 12/06/2013
alopez: 7/9/2013
alopez: 7/8/2013
alopez: 6/20/2013
alopez: 2/6/2013
ckniffin: 1/30/2013
carol: 7/26/2012
carol: 7/25/2012
ckniffin: 7/25/2012
alopez: 7/19/2012
terry: 7/17/2012
terry: 7/3/2012
carol: 7/2/2012
ckniffin: 6/28/2012
terry: 4/9/2012
alopez: 3/7/2012
carol: 12/8/2011
carol: 11/29/2011
terry: 3/10/2011
wwang: 3/1/2011
ckniffin: 2/21/2011
alopez: 2/7/2011
terry: 2/3/2011
terry: 11/3/2010
alopez: 8/20/2010
terry: 8/17/2010
alopez: 3/9/2010
terry: 3/9/2010
alopez: 1/6/2010
terry: 12/29/2009
carol: 11/23/2009
wwang: 11/6/2009
ckniffin: 10/27/2009
alopez: 10/23/2009
terry: 10/13/2009
joanna: 9/14/2009
wwang: 6/3/2009
terry: 6/1/2009
wwang: 3/5/2009
ckniffin: 3/3/2009
alopez: 2/6/2009
carol: 2/6/2009
terry: 1/20/2009
alopez: 7/31/2008
terry: 7/29/2008
wwang: 3/19/2008
ckniffin: 3/17/2008
alopez: 11/14/2007
terry: 11/12/2007
carol: 9/10/2007
carol: 9/6/2007
alopez: 4/13/2007
terry: 4/5/2007
carol: 3/8/2007
ckniffin: 3/8/2007
ckniffin: 3/2/2007
wwang: 2/19/2007
ckniffin: 2/15/2007
alopez: 2/8/2007
terry: 2/1/2007
alopez: 12/7/2006
terry: 11/28/2006
alopez: 6/16/2006
terry: 6/13/2006
mgross: 4/14/2006
terry: 4/10/2006
wwang: 3/30/2006
terry: 3/28/2006
alopez: 3/3/2006
terry: 2/24/2006
alopez: 9/14/2005
terry: 9/7/2005
alopez: 7/14/2005
carol: 5/27/2005
mgross: 3/28/2005
tkritzer: 3/22/2005
tkritzer: 12/16/2003
cwells: 11/6/2003
alopez: 9/2/2003
terry: 1/2/2003
terry: 11/22/2002
alopez: 9/17/2002
tkritzer: 8/21/2002
tkritzer: 8/19/2002
terry: 8/15/2002
terry: 3/5/2002
alopez: 2/5/2002
alopez: 1/22/2002
carol: 1/3/2002
mcapotos: 12/19/2001
terry: 12/13/2001
carol: 10/4/2001
mcapotos: 10/3/2001
terry: 9/26/2001
alopez: 9/4/2001
alopez: 8/27/2001
terry: 8/24/2001
alopez: 4/25/2001
terry: 4/23/2001
alopez: 5/1/2000
terry: 4/28/2000
alopez: 2/15/2000
terry: 2/11/2000
mgross: 6/22/1999
alopez: 9/22/1998
terry: 7/24/1998
dkim: 7/23/1998
psherman: 3/27/1998
dholmes: 3/6/1998
alopez: 11/26/1997
alopez: 11/17/1997
alopez: 11/14/1997
mark: 3/3/1997
mark: 1/10/1997
terry: 11/6/1996
terry: 10/31/1996
mark: 8/10/1995
mimadm: 6/7/1995
carol: 11/1/1993
carol: 6/30/1993
carol: 6/22/1993
carol: 6/7/1993

MIM 601626
*RECORD*
*FIELD* NO
601626
*FIELD* TI
#601626 LEUKEMIA, ACUTE MYELOID; AML
;;LEUKEMIA, ACUTE MYELOGENOUS
LEUKEMIA, ACUTE MYELOID, SUSCEPTIBILITY TO, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that acute
myeloid leukemia (AML) can be caused by mutations in the CEBPA gene
(116897) and the NPM1 gene (164040).

Somatic mutations in several genes have been found in cases of AML,
e.g., in the CEBPA, ETV6 (600618), JAK2 (147796), KRAS2 (190070), HIPK2
(606868), FLT3 (136351), TET2 (612839), ASXL1 (612990), IDH1 (147700),
CBL (165360), DNMT3A (602769), and SF3B1 (605590) genes. Other causes of
AML include fusion genes generated by chromosomal translocations; see,
for example, 600358 and 159555.

Susceptibility to the development of acute myeloid leukemia may be
caused by germline mutations in certain genes, including GATA2 (137295),
TERC (602322), and TERT (187270).

AML may also be part of the phenotypic spectrum of inherited disorders,
including platelet disorder with associated myeloid malignancy (FPDMM;
601399), caused by mutation in the RUNX1 gene (151385), and
telomere-related pulmonary fibrosis and/or bone marrow failure (PFBMFT1,
614742 and PFBMFT2, 614743), caused by mutation in the TERT or the TERC
gene.

CLINICAL FEATURES

Shields et al. (2003) published a case report on acute myeloid leukemia
that presented as bilateral orbital myeloid sarcoma (or chloroma) in a
previously healthy 25-month-old boy. Bone marrow biopsy revealed blasts
and cells with maturing monocytic features. A final diagnosis of M5b AML
was made. The authors reviewed the literature and concluded that
leukemia may be the most likely diagnosis in a child with bilateral soft
tissue orbital tumors.

CLINICAL MANAGEMENT

AML is often treated with allogeneic hematopoietic stem-cell
transplantation (HSCT), and it is most sensitive to natural killer
(NK)-cell reactivity. Venstrom et al. (2012) assessed clinical data, HLA
genotyping results, and donor cell lines or genomic DNA for 1,277
patients with AML who had received HSCT from unrelated donors matched
for HLA-A, -B, -C, -DR, and -DQ or with a single mismatch. They
performed donor KIR genotyping and evaluated the clinical effect of
donor KIR genotype and donor and recipient HLA genotypes. Patients with
AML who received allografts from donors who were positive for KIR2DS1
(604952) had a lower rate of relapse than those with allografts from
donors who were negative for KIR2DS1 (26.5% vs 32.5%; hazard ratio,
0.76; 95% confidence interval, 0.61 to 0.96; P = 0.02). Of allografts
from donors with KIR2DS1, those from donors who were homozygous or
heterozygous for HLA-C1 antigens could mediate this antileukemic effect,
whereas those from donors who were homozygous for HLA-C2 did not provide
any advantage. Recipients of KIR2DS1-positive allografts mismatched for
a single HLA-C locus had a lower relapse rate than recipients of
KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs
35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P = 0.007). KIR3DS1
(see 604946), in positive genetic linkage disequilibrium with KIR2DS1,
had no effect on leukemia relapse but was associated with decreased
mortality (60.1% vs 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI,
0.71 to 0.96; P = 0.01). Venstrom et al. (2012) concluded that
activating KIR genes from donors were associated with distinct outcomes
of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection
against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was
associated with reduced mortality.

BIOCHEMICAL FEATURES

Garzon et al. (2009) provided evidence supporting a tumor suppressor
role for miR29A (610782) and miR29B (610783) in AML. Overexpression of
both microRNAs reduced cell growth and induced apoptosis in AML cell
lines. Injection of miR29B in a xenograft mouse model of AML resulted in
tumor shrinkage. Northern blot analysis showed that the 2 microRNAs
targeted genes involved in apoptosis, the cell cycle, and cell
proliferation. Transfection of leukemic cells with miR29A and miR29B
resulted in specific downregulation of CXXC6 (TET1; 607790), MCL1
(159552), and CDK6 (603368). Studies of 45 samples from patients with
AML showed an inverse correlation between MCL1 and miR29B. Although 42%
of the miR29A-correlated genes were also correlated with miR29B, there
were some differences: genes related to protein metabolism were found
overrepresented in miR29B-correlated genes, and genes related to immune
function were overrepresented in miR29A-correlated genes. Finally, there
was a downregulation of both miR29A and miR29B in primary AML samples
with monosomy 7 (252270).

CYTOGENETICS

Loss of chromosome 5q is observed in 10 to 15% of patients with
myelodysplastic syndrome (MDS) or acute myeloid leukemia and in 40% of
patients with therapy-related MDS or AML. In addition, patients with 5q
deletion syndrome (153550) show hematologic abnormalities, including
refractory anemia and abnormal megakaryocytes. By cytogenetic analysis
and hybridization techniques, Le Beau et al. (1993) identified a common
2.8-Mb critical region containing the EGR1 gene (128990) on chromosome
5q31 that was deleted in 135 patients with hematologic abnormalities and
5q deletions, including 85 patients with de novo MDS or AML, 33 with
therapy-related MDS or AML, and 17 with MDS and the 5q deletion
syndrome. Le Beau et al. (1993) postulated that EGR1 or another
closely-linked gene may act as a tumor suppressor gene.

Baozhang et al. (1999) reported a family with 7 cases of related
leukemias among 22 members in 3 consecutive generations consistent with
autosomal dominant inheritance. One of the patients and her father were
found to have rearrangement and a rearrangement/amplification,
respectively, of the ERBB oncogene (131550).

Horwitz et al. (1996) reported evidence of anticipation in familial
acute myelogenous leukemia. Horwitz et al. (1996) further studied those
pedigrees and others from the literature. In 49 affected individuals
from 9 families transmitting autosomal dominant AML, the mean age of
onset was 57 years in the grandparental generation, 32 years in the
parental generation, and 13 years in the youngest generation (p less
than 0.001). Horwitz et al. (1996) also reported evidence of
anticipation in autosomal dominant chronic lymphocytic leukemia (CLL;
151400) (p = 0.008). In 18 affected individuals from 7 pedigrees with
autosomal dominant CLL, the mean age of onset in the parental generation
was 66 years, versus 51 years in the younger generation. Based on this
evidence of anticipation, Horwitz et al. (1996) suggested that dynamic
mutations of unstable DNA sequence repeats could be a common mechanism
of inherited hematopoietic malignancy. They proposed 3 possible
candidate chromosomal regions for familial leukemia with anticipation:
21q22.1-22.2, 11q23.3 in the vicinity of the CBL2 gene (165360), and
16q22 in the vicinity of the CBFB gene (121360).

MAPPING

Horwitz et al. (1997) presented evidence suggesting that there is a
locus for acute myelogenous leukemia on chromosome 16q22. They studied a
family with 11 relevant meioses transmitting autosomal dominant AML and
myelodysplasia. They excluded linkage to 21q22.1-q22.2 and to 9p22-p21,
and found a maximum 2-point lod score of 2.82 with the microsatellite
marker D16S522 at recombination fraction theta = 0.0. Haplotype analysis
showed a 23.5-cM region of 16q22 that was inherited in common by all
affected family members and extended from D16S451 to D16S289.
Nonparametric linkage analysis gave a p value of 0.00098 for the
conditional probability of linkage. Mutation analysis excluded expansion
of the AT-rich minisatellite repeat FRA16B fragile site and the CAG
trinucleotide repeat in the E2F-4 transcription factor (600659). The
'repeat expansion detection' method, capable of detecting dynamic
mutation associated with anticipation, more generally excluded large CAG
repeat expansion as a cause of leukemia in this family.

MOLECULAR GENETICS

- Mutations in CEBPA

In affected members of a family with acute myeloid leukemia, Smith et
al. (2004) identified a germline 1-bp deletion (212delC; 116897.0007) in
the CEBPA gene. Overt leukemia developed in the father at age 10 years,
in the first-born son at age 30 years, and in the last-born daughter at
age 18 years.

- Mutations in NPM1

NPM, a nucleocytoplasmic shuttling protein with prominent nucleolar
localization, regulates the ARF (103180)/p53 (191170) tumor suppressor
pathway. Chromosomal translocations involving the NPM gene cause
cytoplasmic dislocation of the NPM protein. Falini et al. (2005) used
immunohistochemical methods to study the subcellular localization of NPM
in bone marrow biopsy specimens from 591 patients with primary AML. They
then correlated the presence of cytoplasmic NPM with clinical and
biologic features of the disease. Cytoplasmic NPM was detected in 35.2%
of the 591 specimens from patients with primary AML but not in 135
secondary AML (sAML) specimens or in 980 hematopoietic or
extrahematopoietic neoplasms other than AML. It was associated with a
wide spectrum of morphologic subtypes of the disease, a normal
karyotype, and responsiveness to induction chemotherapy, but not with
recurrent genetic abnormalities. There was a high frequency of internal
tandem duplications of FLT3 (136351) and absence of CD34 (142230) and
CD133 (604365) in AML specimens with a normal karyotype and cytoplasmic
dislocation of NPM, but not in those in which the protein was restricted
to the nucleus. AML specimens with cytoplasmic NPM carried mutations in
the NPM gene (see 164040.0001-164040.0004); this mutant gene caused
cytoplasmic localization of NPM in transfected cells. All 6 NPM mutant
proteins showed mutations in at least 1 of the tryptophan residues at
positions 288 and 290 and shared the same last 5 amino acid residues
(VSLRK). Thus, despite genetic heterogeneity, all NPM gene mutations
resulted in a distinct sequence in the NPM protein C terminus. Falini et
al. (2005) concluded that cytoplasmic NPM is a characteristic feature of
a large subgroup of patients with AML who have a normal karyotype, NPM
gene mutations, and responsiveness to induction chemotherapy. Grisendi
and Pandolfi (2005) noted that NPM staining in cases of AML with
aberrant cytoplasmic localization of the protein is mostly cytoplasmic,
which suggests that the mutant NPM acts dominantly on the product of the
remaining wildtype allele, causing its retention in the cytoplasm by
heterodimerization.

By microRNA (miRNA) expression profiling, Garzon et al. (2008)
identified 36 upregulated and 21 downregulated miRNAs in AML patients
with NPM1 mutations compared with AML patients without NPM1 mutations.
miR10A (MIRN10A; 610173) and miR10B (MIRN10B; 611576) showed the
greatest upregulation, with increases of 20- and 16.67-fold,
respectively. Mir22 (MIRN22; 612077) showed greatest downregulation,
with a reduction of 0.31-fold. Garzon et al. (2008) concluded that AML
with NPM1 mutations has a distinctive miRNA signature.

- Mutations in GATA2

Hahn et al. (2011) analyzed 50 candidate genes in 5 families with a
predisposition to myelodysplastic syndrome (614286) and acute myeloid
leukemia, and in 3 of the families they identified a heritable
heterozygous missense mutation in the GATA2 gene (T354M; 137295.0002)
that segregated with disease and was not found in 695 nonleukemic
ethnically matched controls.

- Mutations in TERT

Calado et al. (2009) found a significantly increased number of germline
mutations in the TERT gene in patients with sporadic acute myeloid
leukemia compared to controls. One mutation in particular, A1062T
(187270.0022), was 3-fold higher among 594 AML patients compared to
1,110 controls (p = 0.0009). In vitro studies showed that the mutations
caused haploinsufficiency of telomerase activity. An abnormal karyotype
was found in 18 of 21 patients with TERT mutations who were tested.
Calado et al. (2009) suggested that telomere attrition may promote
genomic instability and DNA damage, which may contribute to the
development of leukemia.

- Somatic Mutations

In the bone marrow of a 4-year-old child with AML, Bollag et al. (1996)
identified an insertion in the KRAS2 gene (190070.0008). Expression
studies showed that the mutant KRAS2 protein caused cellular
transformation and activated the RAS-mitogen-activated protein kinase
signaling pathway.

Bone marrow minimal residual disease causes relapse after chemotherapy
in patients with acute myelogenous leukemia. Matsunaga et al. (2003)
postulated that the drug resistance is induced by the attachment of very
late antigen-4 (VLA4; see 192975) on leukemic cells to fibronectin
(135600) on bone marrow stromal cells. Matsunaga et al. (2003) found
that VLA4-positive cells acquired resistance to anoikis (loss of
anchorage) or drug-induced apoptosis through the
phosphatidylinositol-3-kinase (see 601232)/AKT (164730)/Bcl2 (151430)
signaling pathway, which is activated by the interaction of VLA4 and
fibronectin. This resistance was negated by VLA4-specific antibodies. In
a mouse model of minimal residual disease, Matsunaga et al. (2003)
achieved a 100% survival rate by combining VLA4-specific antibodies and
cytosine arabinoside, whereas cytosine arabinoside alone prolonged
survival only slightly. In addition, overall survival at 5 years was
100% for 10 VLA4-negative patients and 44.4% for 15 VLA4-positive
patients. Thus, Matsunaga et al. (2003) concluded that the interaction
between VLA4 on leukemic cells and fibronectin on stromal cells may be
crucial in bone marrow minimal residual disease and AML prognosis.

Barjesteh van Waalwijk van Doorn-Khosrovani et al. (2005) analyzed 300
patients newly diagnosed with AML for mutations in the coding region of
the ETV6 gene and identified 5 somatic heterozygous mutations (e.g.,
600618.0001 and 600618.0002). These ETV6 mutant proteins were unable to
repress transcription and showed dominant-negative effects. The authors
also examined ETV6 protein expression in 77 patients with AML and found
that 24 (31%) lacked the wildtype 57- and 50-kD proteins; there was no
correlation between ETV6 mRNA transcript levels and the loss of ETV6
protein, suggesting posttranscriptional regulation of ETV6.

Lee et al. (2006) identified heterozygosity for mutations in the JAK2
gene (147796.0001 and 147796.0002) in bone marrow aspirates from 3
(2.7%) of 113 unrelated patients with AML.

Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow
cells from 320 patients with myeloid cancers and identified TET2 defects
in 2 patients with primary AML and 5 patients with secondary AML.

Mardis et al. (2009) used massively parallel DNA sequencing to obtain a
very high level of coverage of a primary, cytogenetically normal, de
novo genome for AML with minimal maturation (AML-M1) and a matched
normal skin genome. Mardis et al. (2009) identified 12 somatic mutations
within the coding sequences of genes and 52 somatic point mutations in
conserved or regulatory portions of the genome. All mutations appeared
to be heterozygous and present in nearly all cells in the tumor sample.
Four of the 64 mutations occurred in at least 1 additional AML sample in
188 samples that were tested. Mutations in NRAS (164790) and NPM1
(164040) had been previously identified in patients with AML, but 2
other mutations had not been identified. One of these mutations, in the
IDH1 (147700) gene, was present in 15 of 187 additional AML genomes
tested and was strongly associated with normal cytogenetic status; it
was present in 13 of 80 cytogenetically normal samples (16%). The other
was a nongenic mutation in a genomic region with regulatory potential
and conservation in higher mammals; it is at position 108,115,590 of
chromosome 10. The AML genome that was sequenced contained approximately
750 point mutations, of which only a small fraction are likely to be
relevant to pathogenesis.

Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene
(612990) may act as a tumor suppressor in myeloid malignancies. They
identified heterozygous somatic mutations in the ASXL1 gene in 5 (16%)
of 38 myelodysplastic syndrome/acute myeloid leukemia samples. Somatic
ASXL1 mutations were also found in 19 (43%) of 44 chronic myelomonocytic
leukemia (CMML; see 607785) samples. All the mutations were in exon 12
and resulted in truncation of the C-terminal PHD finger of the protein.
The findings suggested that regulators of gene expression via DNA
methylation, histone modification, and chromatin remodeling could be
altered in myelodysplastic syndromes and some leukemias. The same group
(Carbuccia et al., 2009) identified heterozygous somatic truncating
ASXL1 mutations in 5 (7.8%) of 64 myeloproliferative neoplasms,
including 1 essential thrombocythemia (187950), 3 primary myelofibrosis
(254450), and 1 AML.

Harutyunyan et al. (2011) analyzed biopsy specimens of
myeloproliferative neoplastic tissue from 330 patients for chromosomal
aberrations associated with leukemic transformation. Three hundred and
eight of the patients had chronic-phase myeloproliferative neoplasms and
22 had postmyeloproliferative-phase neoplasm secondary acute myeloid
leukemia. Among those 22 patients, 1 carried the MPL W515L mutation and
all others carried the JAK2 V617F mutation. Six of the 22 patients
carried somatic mutations of TP53 (191170). Three of the patients had
independent mutations on both TP53 alleles, and 2 had homozygous
mutations because of an acquired uniparental disomy of chromosome 17p.
None of the patients with TP53 mutations had amplification of chromosome
1q involving the MDM4 gene (604704). Harutyunyan et al. (2011) concluded
that TP53 mutations are strongly associated with transformation to AML
in patients with myeloproliferative neoplasms (p = 0.003). Harutyunyan
et al. (2011) also found amplification of a region of chromosome 1q
harboring the MDM4 gene in 18.18% of patients with secondary AML (p less
than 0.001).

Ding et al. (2012) determined the mutational spectrum associated with
relapse of AML by sequencing the primary tumor and relapse genomes from
8 AML patients, and validated hundreds of somatic mutations using deep
sequencing. This method allowed them to define clonality and clonal
evolution patterns precisely at relapse. In addition to discovering
novel, recurrently mutated genes (e.g., WAC; SMC3, 606062; DIS3, 607533;
DDX41, 608170; and DAXX, 603186) in AML, Ding et al. (2012) identified 2
major clonal evolution patterns during AML relapse: (1) the founding
clone in the primary tumor gained mutations and evolved into the relapse
clone, or (2) a subclone of the founding clone survived initial therapy,
gained additional mutations, and expanded at relapse. In all cases,
chemotherapy failed to eradicate the founding clone. The comparison of
relapse-specific versus primary tumor mutations in all 8 cases revealed
an increase in transversions, probably due to DNA damage caused by
cytotoxic chemotherapy. Ding et al. (2012) concluded that AML relapse is
associated with the addition of new mutations and clonal evolution,
which is shaped, in part, by the chemotherapy that the patients receive
to establish and maintain remissions.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. A total of 23 genes were significantly mutated, and another
237 were mutated in 2 or more samples. Nearly all samples had at least 1
nonsynonymous mutation in 1 of 9 categories of genes that were deemed
relevant for pathogenesis. The authors identified recurrent mutations in
the NPM1 gene in 54/200 (27%) samples, in the FLT3 gene (136351) in
56/200 (28%) samples, in the DNMT3A gene (602769) in 51/200 (26%)
samples, and in the IDH1 or IDH2 (147650) genes in 39/200 (20%) samples.

Brewin et al. (2013) noted that the study of the Cancer Genome Atlas
Research Network (2013) did not reveal which mutations occurred in the
founding clone, as would be expected for an initiator of disease, and
which occurred in minor clones, which subsequently drive disease. Miller
et al. (2013) responded that genes mutated almost exclusively in
founding clones in their study included RUNX1 (151385) (9 of 9 mutations
in founding clones), NPM1 (164040) (3 of 3 clones), U2AF1 (191317) (5 of
5 clones), DNMT3A (38 of 40 clones), IDH2 (13 of 14), IDH1 (147700) (15
of 17 clones), and KIT (164920) (5 of 6). In contrast, mutations in
NRAS, TET2 (612839), CEBPA, WT1 (607102), PTPN11 (176876), and FLT3 were
often found in subclones, suggesting that they were often cooperating
mutations.

GENOTYPE/PHENOTYPE CORRELATIONS

Schlenk et al. (2008) studied 872 patients younger than 60 years of age
with cytogenetically normal AML and compared mutation status of the NPM1
(164040), FLT3 (136351), CEBPA (116897), MLL (159555), and NRAS (164790)
genes in leukemia cells with clinical outcome. There was an overall
complete remission rate of 77%. The genotype of mutant NPM1 without FLT3
internal tandem duplications (FLT3-ITD), the mutant CEBPA genotype, and
younger age were each significantly associated with complete remission.
The authors also found that the benefit of postremission hematopoietic
stem cell transplant was limited to the subgroup of patients with the
prognostically adverse genotype FLT3-ITD or the genotype consisting of
wildtype NPM1 and CEBPA without FLT3-ITD.

Gale et al. (2008) found that 354 (26%) of 1,425 patients with AML had
the FLT3 internal duplication. The median total mutant level for all
patients was 35% of total FLT3, but there was wide variation with levels
ranging from 1 to 96%. There was a significant correlation between worse
overall survival, relapse risk, and increased white blood cell count
with increased mutant level, but the size of the duplication and the
number of mutations had no significant impact on outcome. Those patients
with the FLT3 duplication had a worse risk of relapse than patients
without the FLT3 duplication. Among a subset of 1,217 patients, 503
(41%) had a mutation in the NPM1 gene (164040), and 208 (17%) had
mutations in both genes. The presence of an NPM1 mutation had a
beneficial effect on the remission rate, most likely due to a lower rate
of resistant disease, both in patients with and without FLT3
duplications. Gale et al. (2008) identified 3 prognostic groups among
AML patients: good in those with only a NPM1 mutation; intermediate in
those with either no FLT3 or NPM1 mutations or mutations in both genes;
and poor in those with only FLT3 mutations.

Boissel et al. (2011) reviewed the work of several others and performed
their own analysis of 205 patients with cytogenetically normal AML, and
found that patients with IDH2(R172) mutations had a worse prognosis from
those with IDH2(R140) mutations (e.g., 147650.0001). That patients with
IDH2(R172) mutations had an unfavorable prognosis by comparison had been
noted by Marcucci et al. (2010). The frequency of IDH2(R172) mutations
was lower than that of IDH2(R140) mutations among cytogenetically normal
AML patients. Boissel et al. (2011) cautioned that patients should be
separated by mutation status for prognostic analysis.

Activating internal tandem duplication (ITD) mutations in FLT3
(FLT3-ITD) are detected in approximately 20% of acute myeloid leukemia
patients and are associated with a poor prognosis. Abundant laboratory
and clinical evidence, including the lack of convincing clinical
activity of early FLT3 inhibitors, suggested that FLT3-ITD probably
represents a passenger lesion. Smith et al. (2012) reported point
mutations at 3 residues within the kinase domain of FLT3-ITD that confer
substantial in vitro resistance to AC220 (quizartinib), an active
investigational inhibitor of FLT3, KIT (164920), PDGFRA (173490), PDGFRB
(173410), and RET (164761); evolution of AC220-resistant substitutions
at 2 of these amino acids was observed in 8 of 8 FLT3-ITD-positive AML
patients with acquired resistance to AC220. Smith et al. (2012)
concluded that their findings demonstrated that FLT3-ITD can represent a
driver lesion and valid therapeutic target in human AML.

ANIMAL MODEL

Jin et al. (2006) found that treatment with activating monoclonal
antibodies to CD44 (107269) markedly reduced leukemic repopulation in
nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice
challenged with human AML cells. Absence of leukemia following serial
tumor transplantation experiments in mice demonstrated direct targeting
of AML leukemic stem cells (LSCs). Treatment of engrafted mice with
anti-CD44 reduced the number of Cd34 (142230)-positive/Cd38
(107270)-negative primitive stem cells and increased the number of Cd14
(158120)-positive monocytic cells. Anti-CD44 treatment also diminished
the homing capacity of SCID leukemia-initiating cells to bone marrow and
spleen. Jin et al. (2006) concluded that CD44 is a key regulator of AML
LSCs, which require a niche to maintain their stem cell properties. They
suggested that CD44 targeting may help eliminate quiescent AML LSCs.

Mullican et al. (2007) generated Nr4a1 (139139)/Nr4a3 (600542)
double-null mice and observed the development of rapidly lethal acute
myeloid leukemia involving abnormal expansion of hematopoietic stem
cells and myeloid progenitors, decreased expression of JunB (165161) and
c-Jun (165160), and defective extrinsic apoptotic signaling (FASL,
134638; TRAIL, 603598). Leukemic blast cells from 46 AML patients with a
variety of cytogenetic abnormalities all showed downregulation of NR4A1
and NR4A3 compared to CD34+ cells from normal controls, suggesting that
epigenetic silencing of these receptors may be an obligate event in
human AML development.

*FIELD* RF
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2. Barjesteh van Waalwijk van Doorn-Khosrovani, S.; Spensberger, D.;
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mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute
myeloid leukemia. Oncogene 24: 4129-4137, 2005.

3. Boissel, N.; Nibourel, O.; Renneville, A.; Huchette, P.; Dombret,
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in cytogenetically normal acute myeloid leukemia. (Letter) Blood 117:
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4. Bollag, G.; Adler, F.; elMasry, N.; McCabe, P. C.; Connor, E.,
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5. Brewin, J.; Horne, G.; Chevassut, T.: Genomic landscapes and clonality
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6. Calado, R. T.; Regal, J. A.; Hills, M.; Yewdell, W. T.; Dalmazzo,
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13. Garzon, R.; Garofalo, M.; Martelli, M. P.; Briesewitz, R.; Wang,
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14. Garzon, R.; Heaphy, C. E. A.; Havelange, V.; Fabbri, M.; Volinia,
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15. Gelsi-Boyer, V.; Trouplin, V.; Adelaide, J.; Bonansea, J.; Cervera,
N.; Carbuccia, N.; Lagarde, A.; Prebet, T.; Nezri, M.; Sainty, D.;
Olschwang, S.; Xerri, L.; Chaffanet, M.; Mozziconacci, M.-J.; Vey,
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myelodysplastic syndromes and chronic myelomonocytic leukaemia. Brit.
J. Haemat. 145: 788-800, 2009.

16. Grisendi, S.; Pandolfi, P. P.: NPM mutations in acute myelogenous
leukemia. (Editorial) New Eng. J. Med. 352: 291-292, 2005.

17. Hahn, C. N.; Chong, C.-E.; Carmichael, C. L.; Wilkins, E. J.;
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18. Harutyunyan, A.; Klampfl, T.; Cazzola, M.; Kralovics, R.: p53
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19. Horwitz, M.; Benson, K. F.; Li, F.-Q.; Wolff, J.; Leppert, M.
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22. Jin, L.; Hope, K. J.; Zhai, Q.; Smadja-Joffe, F.; Dick, J. E.
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23. Le Beau, M. M.; Espinosa, R., III; Neuman, W. L.; Stock, W.; Roulston,
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25. Marcucci, G.; Maharry, K.; Wu, Y.-Z.; Radmacher, M. D.; Mrozek,
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26. Mardis, E. R.; Ding, L.; Dooling, D. J.; Larson, D. E.; McLellan,
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2012.

*FIELD* CS

Heme:
Familial acute myelogenous leukemia (AML)

Misc:
Evidence of anticipation;
Mean onset age 57 years, 32 years and 13 years in successive generations

Inheritance:
Autosomal dominant

*FIELD* CD
John F. Jackson: 09/23/1998

*FIELD* CN
Ada Hamosh - updated: 11/25/2013
Ada Hamosh - updated: 7/9/2013
Ada Hamosh - updated: 9/6/2012
Cassandra L. Kniffin - updated: 8/2/2012
Ada Hamosh - updated: 6/27/2012
Ada Hamosh - updated: 2/8/2012
Marla J. F. O'Neill - updated: 11/2/2011
Ada Hamosh - updated: 10/4/2011
Cassandra L. Kniffin - updated: 5/4/2011
Ada Hamosh - updated: 2/15/2011
Cassandra L. Kniffin - updated: 12/16/2010
Cassandra L. Kniffin - updated: 10/6/2009
Ada Hamosh - updated: 9/15/2009
Marla J. F. O'Neill - updated: 6/10/2009
Cassandra L. Kniffin - updated: 7/30/2008
Patricia A. Hartz - updated: 6/9/2008
Marla J. F. O'Neill - updated: 5/14/2008
Cassandra L. Kniffin - updated: 3/26/2008
Marla J. F. O'Neill - updated: 7/2/2007
Paul J. Converse - updated: 11/17/2006
Cassandra L. Kniffin - updated: 6/20/2006
Marla J. F. O'Neill - updated: 4/12/2006
Ada Hamosh - updated: 8/26/2003
Victor A. McKusick - updated: 11/17/1999

*FIELD* CD
Moyra Smith: 1/14/1997

*FIELD* ED
carol: 12/06/2013
alopez: 11/25/2013
alopez: 7/9/2013
alopez: 4/15/2013
alopez: 9/10/2012
terry: 9/6/2012
carol: 8/6/2012
ckniffin: 8/2/2012
alopez: 7/3/2012
terry: 6/27/2012
alopez: 2/10/2012
terry: 2/8/2012
carol: 1/30/2012
carol: 11/2/2011
ckniffin: 10/24/2011
alopez: 10/11/2011
terry: 10/7/2011
terry: 10/4/2011
wwang: 5/19/2011
wwang: 5/11/2011
ckniffin: 5/4/2011
ckniffin: 5/2/2011
alopez: 2/17/2011
terry: 2/15/2011
carol: 12/16/2010
ckniffin: 12/16/2010
carol: 7/2/2010
alopez: 1/28/2010
wwang: 10/14/2009
ckniffin: 10/6/2009
alopez: 9/16/2009
terry: 9/15/2009
wwang: 6/12/2009
terry: 6/10/2009
ckniffin: 6/9/2009
wwang: 12/5/2008
ckniffin: 12/3/2008
mgross: 10/9/2008
wwang: 8/1/2008
ckniffin: 7/30/2008
mgross: 6/9/2008
carol: 5/14/2008
wwang: 4/8/2008
ckniffin: 3/26/2008
wwang: 7/5/2007
terry: 7/2/2007
ckniffin: 3/1/2007
mgross: 11/17/2006
wwang: 6/23/2006
ckniffin: 6/20/2006
wwang: 4/12/2006
terry: 4/12/2006
mgross: 5/17/2005
tkritzer: 2/7/2005
alopez: 9/2/2003
alopez: 8/26/2003
terry: 8/26/2003
carol: 11/13/2001
mgross: 12/6/1999
terry: 11/17/1999
mark: 1/14/1997

MIM 607785
*RECORD*
*FIELD* NO
607785
*FIELD* TI
#607785 JUVENILE MYELOMONOCYTIC LEUKEMIA; JMML
;;LEUKEMIA, JUVENILE MYELOMONOCYTIC
read moreLEUKEMIA, CHRONIC MYELOMONOCYTIC, INCLUDED; CMML, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because juvenile
myelomonocytic leukemia (JMML) can be caused by somatic mutations in
specific genes that result in activation of the RAS signaling pathway,
such as PTPN11 (176876), KRAS (190070), NRAS (164790). Somatic mutation
in the CBL gene (165360) has also been reported.

DESCRIPTION

Juvenile myelomonocytic leukemia is an aggressive pediatric
myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD)
characterized by malignant transformation in the hematopoietic stem cell
compartment with proliferation of differentiated progeny (Loh et al.,
2009). JMML constitutes approximately 30% of childhood cases of
myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999).
Although JMML is a progressive and often rapidly fatal disease without
hematopoietic stem cell transplantation (HSCT), some patients have been
shown to have a prolonged and stable clinical course without HSCT
(Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a
similar disorder with later onset. Both JMML and CMML have a high
frequency of mutations affecting the RAS signaling pathway and show
hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511)
hyperphosphorylation (Loh et al., 2009).

- Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia

In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due
to somatic mutations in the PTPN11, KRAS, and NRAS genes. Additionally,
both germline and somatic mutations in the CBL gene have been found in
patients with JMML, indicating a frequency of 10 to 15% of JMML patients
overall (Loh et al., 2009). Somatic disruptions of the GRAF gene
(ARHGAP26; 605370) have also been found in patients with JMML.

About 10 to 15% of JMML cases arise in children with neurofibromatosis
type I (NF1; 162200) due to germline mutations in the NF1 gene (613113).
In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or
Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations
in the PTPN11, KRAS2, and CBL genes, respectively, also have an
increased risk of developing JMML.

- Genetic Heterogeneity of Chronic Myelomonocytic Leukemia

Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1
(605590) genes have been found in patients with CMML.

CYTOGENETICS

In a patient with chronic myelomonocytic leukemia (CMML) with a
t(5;7)(q33;q11.2) translocation, Ross et al. (1998) found fusion of the
HIP1 gene (601767) to the platelet-derived growth factor-beta receptor
gene (PDGFRB; 173410). They identified a chimeric transcript containing
the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The
fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the
transmembrane and tyrosine kinase domains of the PDGFRB gene. The
reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein
product was a 180-kD protein when expressed in a murine hematopoietic
cell line and was constitutively tyrosine phosphorylated. Furthermore,
the fusion gene transformed the same mouse hematopoietic cell line to
interleukin-3-independent growth.

In a patient with CMML and an acquired t(5;17)(q33;p13), Magnusson et
al. (2001) demonstrated rabaptin-5 (RABEP1; 603616) as a novel partner
fused in-frame to the 5-prime portion of the PDGFBR gene (173410). The
fusion protein included more than 85% of the native rabaptin-5 fused to
the transmembrane and intracellular tyrosine kinase domains of PDGFRB.
Rabaptin-5 is an essential and rate-limiting component of early
endosomal fusion. The new fusion protein links 2 important pathways of
growth regulation.

MOLECULAR GENETICS

- Mutations Associated with Noonan Syndrome and JMML

Tartaglia et al. (2003) showed that germline mutations in PTPN11 lead to
Noonan syndrome-1 (NS1; 163950) associated with JMML (T73I;
176876.0011), and that somatic mutations in PTPN11 are associated with
isolated JMML. Jongmans et al. (2005) described a patient with Noonan
syndrome and mild JMML who carried a mutation in the PTPN11 gene
(176876.0011).

Schubbert et al. (2006) described a 3-month-old female with Noonan
syndrome-3 (NS3; 609942) and a severe clinical phenotype who presented
with a JMML-like myeloproliferative disorder. The patient was
heterozygous for a mutation in the KRAS gene (T58I; 190070.0011). This
mutation was also present in her buccal cells, but was absent in
parental DNA.

De Filippi et al. (2009) reported a boy who presented in infancy with
JMML and was later noted to have dysmorphic features suggestive of, but
not diagnostic of, Noonan syndrome (see NS6; 613224). Features included
short stature, relative macrocephaly, high forehead, epicanthal folds,
long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and
low scores on performance tasks. Cardiac studies were normal. Genetic
analysis revealed a de novo germline heterozygous mutation in the NRAS
gene (G13D; 164790.0003).

In 3 unrelated patients with a Noonan syndrome-like disorder (613563)
who developed JMML, Perez et al. (2010) identified a heterozygous
germline mutation in the CBL gene (Y371H; 165360.0005). The mutation
occurred de novo in 2 patients and was inherited from an unaffected
father in 1 patient. Leukemia cells of all patients showed somatic loss
of heterozygosity at chromosome 11q23, including the CBL gene. The
findings indicated that germline heterozygous mutations in the CBL gene
are associated with predisposition for the development of JMML.

In 27 of 159 leukemia samples from patients with JMML, Loh et al. (2009)
identified 25 homozygous and 2 heterozygous mutations in the CBL gene.
The mutations were located throughout the linker and RING finger
domains, and Y371H was the most common mutation. Leukemic cells from 3
patients examined in detail had acquired isodisomy of chromosome 11q
including the CBL gene. Each of these 3 patients had a heterozygous
germline CBL mutation, whereas their tumor cells had homozygous
mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high
levels of STAT5 (601511) in response to GM-CSF. These findings indicated
that reduplication of an inherited CBL mutation in a pluripotent
hematopoietic stem cell confers a selective advantage for the homozygous
state. Loh et al. (2009) estimated the frequency of CBL mutations to be
10 to 15% of JMML patients overall. They did not find CBL mutations in
JMML patients with known PTPN11/RAS mutation, indicating that CBL and
PTPN11/RAS mutations are mutually exclusive. The finding that
heterozygous germline mutations may predispose to development of JMML
suggested that CBL acts as a tumor suppressor gene.

- Isolated Juvenile or Chronic Myelomonocytic Leukemia

Jankowska et al. (2009) identified recurrent areas of somatic copy
number-neutral loss of heterozygosity (LOH) and deletions of chromosome
4q24 in patients with MDS/MPD. Subsequent analysis identified somatic
mutations in the TET2 gene (612839) in 6 of 17 cases of chronic
myelomonocytic leukemia.

Abdel-Wahab et al. (2009) identified somatic mutations in the TET2 gene
in 29 (42%) of 69 CMML.

Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene
(612990) may act as a tumor suppressor in myeloid malignancies. They
identified somatic ASXL1 mutations were also found in 19 (43%) of 44
chronic myelomonocytic leukemia samples.

Loh et al. (2009) found isolated CBL mutations in 4 of 44 samples from
patients with CMML, which shares features with JMML.

Muramatsu et al. (2010) identified uniparental disomy of 11q23 in
leukemic cells from 4 of 49 patients with JMML. Mutation analysis of the
CBL gene identified somatic mutations in 5 (10%) of 49 patients.
Mutations in the PTPN11 gene were found in 26 (53%), whereas NRAS and
KRAS mutations were found in 2 (4%) and 1 (2%) patient, respectively.
None of the patients had mutations in the TET2 gene (612839), which had
previously been shown to be present in a significant proportion of
patients with MDS/MPD, including CMML (see Jankowska et al., 2009).
Eighteen (37%) of the 49 patients with JMML studied by Muramatsu et al.
(2010) did not have any of the known pathogenic defects.

Klinakis et al. (2011) identified novel somatic-inactivating Notch (see
190198) pathway mutations in a fraction of patients with CMML.
Inactivation of Notch signaling in mouse hematopoietic stem cells
resulted in aberrant accumulation of granulocyte/monocyte progenitors,
extramedullary hematopoiesis, and the induction of CMML-like disease.
Transcriptome analysis revealed that Notch signaling regulates an
extensive myelomonocytic-specific gene signature, through the direct
suppression of gene transcription by the Notch target Hes1 (139605).
Klinakis et al. (2011) concluded that their studies identified a novel
role for Notch signaling during early hematopoietic stem cell
differentiation and suggested that the Notch pathway can play both
tumor-promoting and -suppressive roles within the same tissue.

Sakaguchi et al. (2013) performed whole-exome sequencing for paired
tumor-normal DNA from 13 individuals with JMML (cases), followed by deep
sequencing of 8 target genes in 92 tumor samples. JMML was characterized
by a paucity of gene mutations (0.85 nonsilent mutations per sample)
with somatic or germline RAS pathway involvement in 82 cases (89%). The
SETBP1 (611060) and JAK3 (600173) mutations were among common targets
for secondary mutations. Mutations in JAK3 were often subclonal, and
Sakaguchi et al. (2013) hypothesized that they may be involved in the
progression rather than the initiation of leukemia; these mutations
associated with poor clinical outcomes.

- Exclusion Studies

Yoshida et al. (2008) excluded mutation in the SIPA1 gene (602180) as a
cause of JMML in 16 specimens obtained from patients with the disorder
who did not have mutations in the KRAS, NRAS, or PTPN11 genes.

GENOTYPE/PHENOTYPE CORRELATIONS

Matsuda et al. (2007) reported 3 with patients with an NRAS or KRAS
gly12-to-ser (G12S) mutation who showed spontaneous improvement of
hematologic abnormalities lasting for 2 to 4 years with neither
intensive therapy nor HSCT. They suggested that the mild course
correlated with the G12S RAS mutation and recommended that patients
found to have this mutation receive close follow-up but no chemotherapy.
Flotho et al. (2008) viewed the recommendation of Matsuda et al. (2007)
as premature. They reviewed 50 patients with JMML who were not given
HSCT within the first 3 years after diagnosis; of these, 17 survived
without treatment from 4 to 21 years. Six of 7 carried a RAS mutation
different from R12S.

*FIELD* RF
1. Abdel-Wahab, O.; Mullally, A.; Hedvat, C.; Garcia-Manero, G.; Patel,
J.; Wadleigh, M.; Malinge, S.; Yao, J.; Kilpivaara, O.; Bhat, R.;
Huberman, K.; Thomas, S.; and 12 others: Genetic characterization
of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114:
144-147, 2009.

2. De Filippi, P.; Zecca, M.; Lisini, D.; Rosti, V.; Cagioni, C.;
Carlo-Stella, C.; Radi, O.; Veggiotti, P.; Mastronuzzi, A.; Acquaviva,
A.; D'Ambrosio, A.; Locatelli, F.; Danesino, C.: Germ-line mutation
of the NRAS gene may be responsible for the development of juvenile
myelomonocytic leukaemia. Brit. J. Haematol. 147: 706-709, 2009.

3. Flotho, C.; Kratz, C. P.; Bergstrasser, E.; Hasle, H.; Stary, J.;
Trebo, M.; van den Heuvel-Eibrink, M. M.; Wojcik, D.; Zecca, M.; Locatelli,
F.; Niemeyer, C. M.: Genotype-phenotype correlation in cases of juvenile
myelomonocytic leukemia with clonal RAS mutations. (Letter) Blood 111:
966-967, 2008.

4. Gelsi-Boyer, V.; Trouplin, V.; Adelaide, J.; Bonansea, J.; Cervera,
N.; Carbuccia, N.; Lagarde, A.; Prebet, T.; Nezri, M.; Sainty, D.;
Olschwang, S.; Xerri, L.; Chaffanet, M.; Mozziconacci, M.-J.; Vey,
N.; Birnbaum, D.: Mutations of polycomb-associated gene ASXL1 in
myelodysplastic syndromes and chronic myelomonocytic leukaemia. Brit.
J. Haemat. 145: 788-800, 2009.

5. Hasle, H.; Arico, M.; Basso, G.; Biondi, A.; Rajnoldi, A. C.; Creutzig,
U.; Fenu, S.; Fonatsch, C.; Haas, O. A.; Harbott, J.; Kardos, G.;
Kerndrup, G.; and 11 others: Myelodysplastic syndrome, juvenile
myelomonocytic leukemia, and acute myeloid leukemia associated with
complete or partial monosomy 7. Leukemia 13: 376-385, 1999.

6. Jankowska, A. M.; Szpurka, H.; Tiu, R. V.; Makishima, H.; Afable,
M.; Huh, J.; O'Keefe, C. L.; Ganetzky, R.; McDevitt, M. A.; Maciejewski,
J. P.: Loss of heterozygosity 4q24 and TET2 mutations associated
with myelodysplastic/myeloproliferative neoplasms. Blood 113: 6403-6410,
2009.

7. Jongmans, M.; Sistermans, E. A.; Rikken, A.; Nillesen, W. M.; Tamminga,
R.; Patton, M.; Maier, E. M.; Tartaglia, M.; Noordam, K.; van der
Burgt, I.: Genotypic and phenotypic characterization of Noonan syndrome:
new data and review of the literature. Am. J. Med. Genet. 134A:
165-170, 2005.

8. Klinakis, A.; Lobry, C.; Abdel-Wahab, O.; Oh, P.; Haeno, H.; Buonamici,
S.; van De Walle, I.; Cathelin, S.; Trimarchi, T.; Araldi, E.; Liu,
C.; Ibrahim, S.; Beran, M.; Zavadil, J.; Efstratiadis, A.; Taghon,
T.; Michor, F.; Levine, R. L.; Aifantis, I.: A novel tumour-suppressor
function for the Notch pathway in myeloid leukaemia. Nature 473:
230-233, 2011.

9. Loh, M. L.; Sakai, D. S.; Flotho, C.; Kang, M.; Fliegauf, M.; Archambeault,
S.; Mullighan, C. G.; Chen, L.; Bergstraesser, E.; Bueso-Ramos, C.
E.; Emanuel, P. D.; Hasle, H.; and 9 others: Mutations in CBL occur
frequently in juvenile myelomonocytic leukemia. Blood 114: 1859-1863,
2009.

10. Magnusson, M. K.; Meade, K. E.; Brown, K. E.; Arthur, D. C.; Krueger,
L. A.; Barrett, A. J.; Dunbar, C. E.: Rabaptin-5 is a novel fusion
partner to platelet-derived growth factor beta receptor in chronic
myelomonocytic leukemia. Blood 98: 2518-2525, 2001.

11. Matsuda, K.; Shimada, A.; Yoshida, N.; Ogawa, A.; Watanabe, A.;
Yajima, S.; Iizuka, S.; Koike, K.; Yanai, F.; Kawasaki, K.; Yanagimachi,
M.; Kikuchi, A.; and 10 others: Spontaneous improvement of hematologic
abnormalities in patients having juvenile myelomonocytic leukemia
with specific RAS mutations. Blood 109: 5477-5480, 2007.

12. Muramatsu, H.; Makishima, H.; Jankowska, A. M.; Cazzolli, H.;
O'Keefe, C.; Yoshida, N.; Xu, Y.; Nishio, N.; Hama, A.; Yagasaki,
H.; Takahashi, Y.; Kato, K.; Manabe, A.; Kojima, S.; Maciejewski,
J. P.: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations
are pathogenic in juvenile myelomonocytic leukemia. Blood 115: 1969-1975,
2010.

13. Niemeyer, C. M.; Arico, M.; Basso, G.; Biondi, A.; Cantu Rajnoldi,
A.; Creutzig, U.; Haas, O.; Harbott, J.; Hasle, H.; Kerndrup, G.;
Locatelli, F.; Mann, G.; Stollmann-Gibbels, B.; van't Veer-Korthof,
E. T.; van Wering, E.; Zimmermann, M.; European Working Group on
Myelodysplastic Syndromes in Childhood (EWOG-MDS): Chronic myelomonocytic
leukemia in childhood: a retrospective analysis of 110 cases. Blood 89:
3534-3543, 1997.

14. Perez, B.; Mechinaud, F.; Galambrun, C.; Ben Romdhane, N.; Isidor,
B.; Philip, N.; Derain-Court, J.; Cassinat, B.; Lachenaud, J.; Kaltenbach,
S.; Salmon, A.; Desiree, C.; Pereira, S.; Menot, M. L.; Royer, N.;
Fenneteau, O.; Baruchel, A.; Chomienne, C.; Verloes, A.; Cave, H.
: Germline mutations of the CBL gene define a new genetic syndrome
with predisposition to juvenile myelomonocytic leukaemia. J. Med.
Genet. 47: 686-691, 2010.

15. Ross, T. S.; Bernard, O. A.; Berger, R.; Gilliland, D. G.: Fusion
of huntingtin interacting protein 1 to platelet-derived growth factor-beta
receptor (PDGF-beta-R) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 91:
4419-4426, 1998.

16. Sakaguchi, H.; Okuno, Y.; Muramatsu, H.; Yoshida, K.; Shiraishi,
Y.; Takahashi, M.; Kon, A.; Sanada, M.; Chiba, K.; Tanaka, H.; Makishima,
H.; Wang, X.; and 10 others: Exome sequencing identifies secondary
mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nature
Genet. 45: 937-941, 2013.

17. Schubbert, S.; Zenker, M.; Rowe, S. L.; Boll, S.; Klein, C.; Bollag,
G.; van der Burgt, I.; Musante, L.; Kalscheuer, V.; Wehner, L.-E.;
Nguyen, H.; West, B.; Zhang, K. Y. J.; Sistermans, E.; Rauch, A.;
Niemeyer, C. M.; Shannon, K.; Kratz, C. P.: Germline KRAS mutations
cause Noonan syndrome. Nature Genet. 38: 331-336, 2006. Note: Erratum:
Nature Genet. 38: 598 only, 2006.

18. Tartaglia, M.; Niemeyer, C. M.; Fragale, A.; Song, X.; Buechner,
J.; Jung, A.; Hahlen, K.; Hasle, H.; Licht, J. D.; Gelb, B. D.: Somatic
mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic
syndromes and acute myeloid leukemia. Nature Genet. 34: 148-150,
2003.

19. Yoshida, N.; Yagasaki, H.; Takahashi, Y.; Kudo, K.; Manabe, A.;
Kojima, S.: Mutation analysis of SIPA1 in patients with juvenile
myelomonocytic leukemia. (Letter) Brit. J. Haematol. 142: 845-846,
2008.

*FIELD* CN
Ada Hamosh - updated: 01/28/2014
Cassandra L. Kniffin - updated: 8/1/2011
Cassandra L. Kniffin - updated: 5/25/2011
Ada Hamosh - updated: 5/23/2011
Cassandra L. Kniffin - updated: 5/3/2011
Carol A. Bocchini - updated: 6/1/2009
Cassandra L. Kniffin - updated: 3/9/2009
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 4/14/2005

*FIELD* CD
Victor A. McKusick: 5/14/2003

*FIELD* ED
alopez: 01/28/2014
carol: 12/8/2011
carol: 11/29/2011
ckniffin: 10/24/2011
wwang: 8/9/2011
ckniffin: 8/1/2011
wwang: 6/2/2011
ckniffin: 5/31/2011
ckniffin: 5/25/2011
alopez: 5/24/2011
terry: 5/23/2011
wwang: 5/19/2011
ckniffin: 5/3/2011
carol: 11/23/2009
terry: 6/19/2009
terry: 6/1/2009
carol: 6/1/2009
wwang: 3/18/2009
ckniffin: 3/9/2009
carol: 7/31/2008
alopez: 3/3/2006
terry: 2/24/2006
tkritzer: 4/27/2005
terry: 4/14/2005
terry: 7/30/2003
alopez: 6/3/2003
alopez: 5/15/2003
alopez: 5/14/2003

MIM 609942
*RECORD*
*FIELD* NO
609942
*FIELD* TI
#609942 NOONAN SYNDROME 3; NS3
*FIELD* TX
A number sign (#) is used with this entry because this form of Noonan
read moresyndrome (NS3) is caused by heterozygous mutation in the KRAS gene
(190070).

DESCRIPTION

Noonan syndrome is an autosomal dominant dysmorphic syndrome
characterized primarily by dysmorphic facial features, cardiac
abnormalities, and short stature, among other features (summary by Shah
et al., 1999).

For a phenotypic description and a discussion of genetic heterogeneity
of Noonan syndrome, see NS1 (163950), which is caused by mutations in
the PTPN11 gene (176876). Approximately 50% of cases of Noonan syndrome
are caused by mutations in PTPN11.

CLINICAL FEATURES

Schubbert et al. (2006) reported a 3-month-old female with Noonan
syndrome without mutation in the PTPN11 gene. She had a severe phenotype
and presented with a juvenile myelomonocytic leukemia-like (JMML;
607785) myeloproliferative disorder. Clinical features included atrial
septal defect, ventricular septal defect, valvular pulmonary stenosis,
dysmorphic facial features, short stature, webbed neck, severe
developmental delay, macrocephaly, and sagittal suture synostosis.

Kratz et al. (2009) reported 2 unrelated patients with Noonan syndrome-3
who also had craniosynostosis. In the first patient, polyhydramnios and
a cystic hygroma were noted during the first trimester. Craniofacial
anomalies included abnormal shape of the skull, frontal bossing,
dolichocephaly, hypertelorism, low-set ears, a short nose with
anteverted nares, and pterygium colli. Cardiac defects included
hypertrophy of the right ventricle and septum, and an open foramen
ovale. Skull imaging showed synostosis of the sagittal suture and parts
of both coronal sutures, necessitating reconstruction. At age 3 years, 2
months, he was unable to sit independently, made little contact, and had
not developed any speech abilities. The second child had a Chiari 1
malformation and closure of the left lamboidal suture that was
surgically corrected at 8 months. Other features included reduced
growth, hypertelorism, epicanthic folds, ptosis, downslanting palpebral
fissures, strabismus, hypoplastic nasal bridge, prominent philtrum, high
palate, low-set and posteriorly rotated ears with a thickened helix, and
mild pectus excavatum. Cardiac features included a dysplastic pulmonary
valve and mild hypertrophy of the interventricular septum. There were
mild cognitive deficits. Kratz et al. (2009) noted that craniosynostosis
is not a commonly recognized feature of Noonan syndrome.

MOLECULAR GENETICS

In a girl with severe Noonan syndrome, Schubbert et al. (2006)
identified a heterozygous de novo mutation in the KRAS gene (T58I;
190070.0011). Analysis of 124 patients with Noonan syndrome without
PTPN11 mutations demonstrated a heterozygous val14-to-ile substitution
in 3 unrelated individuals (V14I; 190070.0012). These individuals showed
a milder clinical phenotype that the patient with the T58I mutation, and
none had a history of myeloproliferative disorder or cancer. Schubbert
et al. (2006) also analyzed 50 additional individuals with Noonan
syndrome and 12 with cardiofaciocutaneous syndrome (CFC; 115150) and
identified KRAS mutations in 1 individual with Noonan syndrome and 1
with CFC. All of these sequence changes occurred de novo, and none was
found in 200 normal European controls.

One of the KRAS sequence changes found by Schubbert et al. (2006) in a
patient with Noonan syndrome was found by Niihori et al. (2006) in a
patient with CFC (190070.0010).

In 2 unrelated children with Noonan syndrome and craniosynostosis, Kratz
et al. (2009) identified 2 different de novo heterozygous mutations in
the KRAS gene (T58I and G60S, 190070.0020). The T58I mutation had
previously been observed in a patient with Noonan syndrome and
craniosynostosis (Schubbert et al., 2006). The findings indicated that
dysregulated RAS signaling may lead to abnormal growth or premature
calvarian closure.

*FIELD* RF
1. Kratz, C. P.; Zampino, G.; Kriek, M.; Kant, S. G.; Leoni, C.; Pantaleoni,
F.; Oudesluys-Murphy, A. M.; Di Rocco, C.; Kloska, S. P.; Tartaglia,
M.; Zenker, M.: Craniosynostosis in patients with Noonan syndrome
caused by germline KRAS mutations. Am. J. Med. Genet. 149A: 1036-1040,
2009.

2. Niihori, T.; Aoki, Y.; Narumi, Y.; Neri, G.; Cave, H.; Verloes,
A.; Okamoto, N.; Hennekam, R. C. M.; Gillessen-Kaesbach, G.; Wieczorek,
D.; Kavamura, M.I.; Kurosawa, K.; and 12 others: Germline KRAS
and BRAF mutations in cardio-facio-cutaneous syndrome. Nature Genet. 38:
294-296, 2006.

3. Schubbert, S.; Zenker, M.; Rowe, S. L.; Boll, S.; Klein, C.; Bollag,
G.; van der Burgt, I.; Musante, L.; Kalscheuer, V.; Wehner, L.-E.;
Nguyen, H.; West, B.; Zhang, K. Y. J.; Sistermans, E.; Rauch, A.;
Niemeyer, C. M.; Shannon, K.; Kratz, C. P.: Germline KRAS mutations
cause Noonan syndrome. Nature Genet. 38: 331-336, 2006. Note: Erratum:
Nature Genet. 38: 598 only, 2006.

4. Shah, N.; Rodriguez, M.; St. Louis, D.; Lindley, K.; Milla, P.
J.: Feeding difficulties and foregut dysmotility in Noonan's syndrome. Arch.
Dis. Child. 81: 28-31, 1999.

*FIELD* CN
Cassandra L. Kniffin - updated: 10/16/2009

*FIELD* CD
Anne M. Stumpf: 3/3/2006

*FIELD* ED
wwang: 05/18/2011
carol: 10/8/2010
alopez: 1/28/2010
wwang: 11/6/2009
ckniffin: 10/16/2009
alopez: 3/3/2006

MIM 613659
*RECORD*
*FIELD* NO
613659
*FIELD* TI
#613659 GASTRIC CANCER
GASTRIC CANCER, INTESTINAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because somatic mutations in
read morevarious genes have been identified in gastric cancer tumor tissue. These
genes include APC (611731), IRF1 (147575), KLF6 (602053), MUTYH
(604933), KRAS (190070), CASP10 (601762), PIK3CA (171834), ERBB2
(164870), and FGFR2 (176943).

DESCRIPTION

In a review article on the genetic predisposition to gastric cancer,
Bevan and Houlston (1999) concluded that several genes may be associated
with an increased risk of gastric cancer.

Gastric cancer is a manifestation of a number of inherited cancer
predisposition syndromes, including hereditary nonpolyposis colon cancer
(HNPCC1; see 120435), familial adenomatous polyposis (FAP; 175100),
Peutz-Jeghers syndrome (PJS; 175200), Cowden disease (CD; 158350), and
the Li-Fraumeni syndrome (151623). See also hereditary diffuse gastric
cancer (HDGC; 137215).

Canedo et al. (2007) provided a review of genetic susceptibility to
gastric cancer in patients infected with Helicobacter pylori (see
600263).

CLINICAL FEATURES

Scott et al. (1990) described a family in which 2 of 4 sibs under the
age of 40 years presented with gastric cancer. A third sib had
antrectomy for gastric dysplasia, and a fourth, aged 36, had extensive
chronic atrophic gastritis and intestinal metaplasia. Of 8 children of
these 4 individuals, 5 had Helicobacter pylori-positive, chronic
atrophic gastritis, and in 3 of the 5, intestinal metaplasia developed
in the gastric antrum but not in the body. Scott et al. (1990)
postulated that the family was segregating a genetic predisposition to
the metaplasia/dysplasia/carcinoma sequence described by Correa (1988).
Helicobacter pylori, previously designated Campylobacter pylori, may
have acted as a promoter in the progression from normal to metaplastic
epithelium, possibly by inducing a hyperproliferative state in the
inflamed gastric mucosa. Scott et al. (1990) noted that the gastric
tumors in this family were consistent with the intestinal type, rather
than the diffuse type.

Kakiuchi et al. (1999) studied the clinical features of the probands of
16 Japanese families with gastric cancer, defined as the existence of 3
or more family members with gastric cancer in at least 2 successive
generations. Seven patients (44%) developed cancer in the cardiac region
of the stomach, which was significantly higher than for gastric cancer
in the general population in Japan (15.4%). The cancers were more often
of the undifferentiated type (69%), and showed an increased frequency of
disseminated peritoneal (40%) and liver metastases (20%) compared to
gastric cancer in the general Japanese population. These unique
characteristics suggested a genetic background in their etiology.

INHERITANCE

Zanghieri et al. (1990) and La Vecchia et al. (1992) found that about
10% of gastric cancer cases show familial clustering. Epidemiologic
studies have shown that the risk of gastric cancer in first-degree
relatives is increased 2- to 3-fold (Goldgar et al., 1994).

In a review, Gonzalez et al. (2002) noted that human gastric
carcinogenesis best fits a multifactorial model, according to which
different dietary and nondietary factors, including genetic
susceptibility, are involved at different stages in the cancer process.

POPULATION GENETICS

Despite a declining incidence (Howson et al., 1986), gastric cancer is a
major cause of cancer death worldwide. Gonzalez et al. (2002) observed
that gastric cancer constitutes the second most frequent cancer in the
world and the fourth in Europe.

In a nationwide epidemiologic study in Sweden, Hemminki and Jiang (2002)
found that the population-attributable proportion of familial gastric
carcinoma was much lower than that cited in the literature. Patterns of
multiple carcinomas suggested that immunologic factors modulate
susceptibility to gastric carcinoma. The authors concluded that
environmental factors, perhaps H. pylori infections, were the main
reason for familial clustering of gastric carcinoma.

PATHOGENESIS

Lauren (1965) defined 2 main histologic types of gastric carcinomas, a
'diffuse' type and a so-called 'intestinal' type. Diffuse tumors, as
observed in hereditary diffuse gastric carcinoma (HDGC; 137215), are
poorly differentiated infiltrating lesions resulting in thickening of
the stomach. In contrast, intestinal tumors are usually exophytic, often
ulcerating, and associated with intestinal metaplasia of the stomach,
most often observed in sporadic disease. This classification system was
updated in 1995 to include 4 main types of gastric cancer: isolated cell
and mixed types (representing the diffuse component); and
glandular/intestinal and solid (representing the non-diffuse component).

The association of gastric cancer with blood group A and pernicious
anemia has been known for a long time. Thomsen et al. (1981) found that
the HLA-DR5 genotype was associated with a 6-fold increase in risk of
pernicious anemia (261000), suggesting that events leading to gastric
cancer have a genetic component.

Palli et al. (2001) evaluated the relation between dietary habits
(particularly consumption of red meat) and MSI status using 126 gastric
cancer cases and 561 population controls identified in a case-control
study carried out in a high-incidence area around Florence, Italy. An
MSI-positive phenotype was detected in 43 of 126 cases (34.1%). A risk
of MSI-positive tumors was positively associated with consumption of red
meat and meat sauce and negatively associated with consumption of white
meat. Risk was especially high among subjects reporting both a positive
family history for gastric cancer and a high consumption of red meat.
The risk of MSI-negative tumors was strongly reduced by the frequent
consumption of fresh fruits and vegetables.

Gonzalez et al. (2002) stated that Helicobacter pylori infection is an
established risk factor of gastric cancer, but gastric cancer occurs in
only a very small proportion of people infected with the organism.
Infection by H. pylori may result in gastric cancer through induced
hyperproliferation of gastric cells, interference with antioxidant
functions, and increased amounts of reactive oxygen species and nitric
oxide, which may be responsible for oxidative DNA damage.

Berman et al. (2003) demonstrated that a wide range of digestive tract
tumors, including most of those originating in the esophagus, stomach,
biliary tract, and pancreas, but not in the colon, display increased
hedgehog pathway activity, which is suppressible by cyclopamine, a
hedgehog pathway antagonist. Cyclopamine also suppresses cell growth in
vitro and causes durable regression of xenograft tumors in vivo. Unlike
tumors in Gorlin syndrome (109400), pathway activity and cell growth in
these digestive tract tumors are driven by endogenous expression of
hedgehog ligands, as indicated by the presence of Sonic hedgehog
(600725) and Indian hedgehog (600726) transcripts, by the pathway- and
growth-inhibitory activity of a hedgehog-neutralizing antibody, and by
the dramatic growth-stimulatory activity of exogenously added hedgehog
ligand. Berman et al. (2003) concluded that their results identified a
group of common lethal malignancies in which hedgehog pathway activity,
essential for tumor growth, is activated not by mutation but by ligand
expression.

Houghton et al. (2004) showed that although acute injury, acute
inflammation, or transient parietal cell loss within the stomach do not
lead to bone marrow-derived stem cell recruitment, chronic infection of
C57BL/6 mice with Helicobacter, a known carcinogen, induced repopulation
of the stomach with such stem cells. Subsequently, these cells
progressed through metaplasia and dysplasia to intraepithelial cancer.
Houghton et al. (2004) suggested that epithelial cancers can originate
from marrow-derived sources and thus have broad implications for the
multistep model of cancer progression.

Chien et al. (2006) studied HTRA1 (PRSS11; 602194) expression in tumors
from 60 patients with epithelial ovarian cancer (167000) and 51 with
gastric cancer and found that those with tumors expressing higher levels
of HTRA1 showed a significantly higher response rate to chemotherapy
than those with lower levels of HTRA1 expression. Chien et al. (2006)
suggested that loss of HTRA1 in ovarian and gastric cancers may
contribute to in vivo chemoresistance.

MAPPING

Loss of heterozygosity at chromosomes 1p, 5q, 7q, 11p, 13q, 17p, and 18p
has been observed in a high proportion of gastric cancer tissues
(Motomura et al., 1988; Kim et al., 1995).

Aoki et al. (2005) performed a genomewide screen for gastric cancer
susceptibility genes in 170 affected sib pairs from 142 Japanese
families. Nonparametric linkage analysis revealed the strongest signal
to be on chromosome 2q33-q35, with multipoint and 2-point lod scores of
1.74 and 1.98, respectively. Analysis of a subgroup with proximal
gastric cancer increased the signal of linkage to 2q33-q35 to multipoint
and 2-point lod scores of 3.61 and 2.93, respectively (p = 0.002 by
simulation studies). Aoki et al. (2005) suggested that there is a
gastric cancer susceptibility locus on chromosome 2q33-q35.

MOLECULAR GENETICS

- Germline Mutations in Cancer Predisposition Syndromes

Carriers of germline mutations in mismatch repair genes (see, e.g.,
MLH1, 120436) have a 4-fold increased risk of gastric cancer in addition
to the high risk of colorectal cancer (Lynch and Smyrk, 1996; Watson and
Lynch, 1993). Mutations in mismatch repair genes result in
microsatellite instability (MSI). Although MSI is seen in 20 to 30% of
cases of gastric cancer (Renault et al., 1996), germline or somatic
mutations in these MMR genes are rarely seen in sporadic or familial
non-HNPCC gastric cancer (Keller et al., 1996). Ottini et al. (1997)
showed that microsatellite instability was significantly associated with
distal (antral) tumors of the stomach and a positive family history of
gastric cancer.

Ottini et al. (1997) showed that microsatellite instability was
significantly associated with distal (antral) tumors of the stomach and
a positive family history of gastric cancer.

Gonzalez et al. (2002) reviewed published evidence on the contribution
of genetic susceptibility to gastric cancer risk in humans. Most of the
studies assessed the effect of genes involved in detoxifying pathways
and inflammatory responses. The most consistent results were the
increased gastric cancer risk associated with interleukin 1-beta (IL1B;
147720) and N-acetyltransferase-1 (NAT1; 108345) variants, which may
account for up to 48% of attributable risk of gastric cancer.
Polymorphisms at the HLA-DQ (146880), tumor necrosis factor (TNF;
(191160), and CYP2E 124040) genes may confer some protective effect
against gastric cancer.

El-Omar et al. (2000) found that individuals carrying the IL1B -31 T
polymorphism (147720.0001) were at a higher risk of hypochlorhydria and
of gastric cancer after H. pylori infection. El-Omar et al. (2000) found
that IL1RN*2 (147679.0001) homozygotes were at increased risk of
hypochlorhydria and gastric cancer. Risk for these disorders among
IL1RN*2 heterozygotes was not significantly increased.

Huntsman et al. (2001) noted that hereditary gastric cancer
predisposition syndromes and CDH1 (192090) germline mutations contribute
very little to the overall load of new gastric cancer cases.

In a 2-stage genomewide association study of Japanese patients with
gastric cancer and controls, the Study Group of Millennium Genome
Project for Cancer (2008) identified a significant association between 2
SNPs in the PSCA gene (602470), dbSNP rs2976392 and dbSNP rs2294008, and
diffuse-type gastric cancer (allele-specific odds ratio = 1.62 and 1.58,
respectively; p = 1.11 x 10(-9) and 6.3 x 10(-9), respectively). The
SNPs were in strong linkage disequilibrium with each other; the authors
noted that in functional studies, the risk allele 'T' of dbSNP rs2294008
reduced transcriptional activity of an upstream fragment of the gene,
suggesting that dbSNP rs2294008 was the functional SNP. The same risk
allele of dbSNP rs2294008 was also significantly associated with
diffuse-type gastric cancer in Korean patients and controls
(allele-specific OR = 1.90; p = 8.01 x 10(-11)). The authors concluded
that polymorphism of the PSCA gene influences susceptibility to
diffuse-type gastric cancer.

In a Korean population, Kwon et al. (2010) presented evidence suggesting
that variation in polymorphic microsatellite repeats in the MUC6 gene
(158374) may influence susceptibility to gastric cancer by regulating
expression of the MUC6 gene.

- Somatic Mutations

Inactivation of the APC gene (611731) is seen in about 20% of early
sporadic gastric cancer (Hsieh and Huang, 1995). Horii et al. (1992)
detected somatic mutations in the APC gene (611731.0010; 611731.0011) in
tumor tissue of 3 of 44 gastric cancers.

In a human gastric cancer cell line, Nozawa et al. (1998) found a
somatic point mutation in the IRF1 gene (147575.0001).

In a set of 80 gastric cancer tissues, Cho et al. (2005) identified 4
somatic missense mutations in the KLF6 gene (see, e.g., 602053.0006);
the mutations were absent from corresponding normal tissue. In addition,
16 (43.2%) of 37 informative cases showed allelic loss at the KLF6
locus. All of the cases with mutation and 13 of the 16 with allelic loss
were of advanced intestinal-type gastric cancer with lymph node
metastasis.

In gastric cancer tissue from 2 unrelated patients who were carriers of
H. pylori, Kim et al. (2004) identified heterozygous somatic mutations
in the MUTYH gene (604933.0006 and 604933.0007, respectively) and loss
of the remaining allele.

Park et al. (2002) identified somatic mutations in the CASP10 gene (see,
e.g., 601762.0004 and 601762.0006) in 3 of 99 gastric cancers.

*FIELD* SA
Caldas et al. (1999)
*FIELD* RF
1. Aoki, M.; Yamamura, Y.; Noshiro, H.; Sakai, K.; Yokota, J.; Kohno,
T.; Tokino, T.; Ishida, S.; Ohyama, S.; Ninomiya, I.; Uesaka, K.;
Kitajima, M.; and 17 others: A full genome scan for gastric cancer.
(Letter) J. Med. Genet. 42: 83-87, 2005.

2. Berman, D. M.; Karhadkar, S. S.; Maitra, A.; Montes de Oca, R.;
Gerstenblith, M. R.; Briggs, K.; Parker, A. R.; Shimada, Y.; Eshleman,
J. R.; Watkins, D. N.; Beachy, P. A.: Widespread requirement for
hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:
846-851, 2003.

3. Bevan, S.; Houlston, R. S.: Genetic predisposition to gastric
cancer. QJM 92: 5-10, 1999.

4. Caldas, C.; Carneiro, F.; Lynch, H. T.; Yokota, J.; Wiesner, G.
L.; Powell, S. M.; Lewis, F. R.; Huntsman, D. G.; Pharoah, P. D. P.;
Jankowski, J. A.; MacLeod, P.; Vogelsang, H.; and 12 others: Familial
gastric cancer: overview and guidelines for management. J. Med. Genet. 36:
873-880, 1999.

5. Canedo, P.; Figueiredo, C.; Machado, J. C.: After Helicobacter
pylori, genetic susceptibility to gastric carcinoma revisited. Helicobacter 12
Suppl. 2: 45-49, 2007.

6. Chien, J.; Aletti, G.; Baldi, A.; Catalano, V.; Muretto, P.; Keeney,
G. L.; Kalli, K. R.; Staub, J.; Ehrmann, M.; Cliby, W. A.; Lee, Y.
K.; Bible, K. C.; Hartmann, L. C.; Kaufmann, S. H.; Shridhar, V.:
Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. J.
Clin. Invest. 116: 1994-2004, 2006.

7. Cho, Y. G.; Kim, C. J.; Park, C. H.; Yang, Y. M.; Kim, S. Y.; Nam,
S. W.; Lee, S. H.; Yoo, N. J.; Lee, J. Y.; Park, W. S.: Genetic alterations
of the KLF6 gene in gastric cancer. Oncogene 24: 4588-4590, 2005.

8. Correa, P.: A human model of gastric carcinogenesis. Cancer Res. 48:
3554-3560, 1988.

9. El-Omar, E. M.; Carrington, M.; Chow, W.-H.; McColl, K. E. L.;
Bream, J. H.; Young, H. A.; Herrera, J.; Lissowska, J.; Yuan, C.-C.;
Rothman, N.; Lanyon, G.; Martin, M.; Fraumeni, J. F., Jr.; Rabkin,
C. S.: Interleukin-1 polymorphisms associated with increased risk
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*FIELD* CD
Cassandra L. Kniffin: 12/1/2010

*FIELD* ED
carol: 03/23/2011
carol: 3/22/2011
terry: 2/28/2011
carol: 12/22/2010
ckniffin: 12/3/2010

MIM 615278
*RECORD*
*FIELD* NO
615278
*FIELD* TI
#615278 CARDIOFACIOCUTANEOUS SYNDROME 2; CFC2
*FIELD* TX
A number sign (#) is used with this entry because this form of
read morecardiofaciocutaneous syndrome (CFC2) is caused by heterozygous mutation
in the KRAS gene (190070) on chromosome 12p12.1.

For a general phenotypic description and a discussion of genetic
heterogeneity of cardiofaciocutaneous syndrome, see CFC1 (115150).

DESCRIPTION

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly
disorder characterized by a distinctive facial appearance, heart
defects, and mental retardation (summary by Niihori et al., 2006). In a
phenotypic comparison of BRAF (164757)-positive and KRAS-positive
individuals with CFC, Niihori et al. (2006) observed that patients with
KRAS mutations did not have the skin abnormalities, such as ichthyosis,
hyperkeratosis, and hemangioma, that were present in patients with BRAF
mutation.

CLINICAL FEATURES

Wieczorek et al. (1997) described a female patient (patient 2) with
cardiofaciocutaneous syndrome. She was noted to be hypotonic in the
first few weeks of life, and early development was complicated by
hypertrophic obstructive cardiomyopathy, atrial septal defect, and
pulmonic stenosis. She walked without support and spoke her first word
at 18 months of age. At age 2.5 the patient could speak only a few
single words. She had short stature, high forehead with bitemporal
constriction, bilateral ptosis, sparse eyebrows and eyelashes, short and
broad-based nose with anteverted nostrils, low-set posteriorly rotated
ears, and sparse, fine, curly hair. The nonconsanguineous mother and
father were 34 and 37 years old, respectively, at the time of the
patient's birth. Wieczorek et al. (1997) also described 2 other
patients, provided a detailed review of previously reported cases, and
discussed the differences from Noonan (see 163950) and Costello (218040)
syndromes.

Stark et al. (2012) reported 3 patients from 2 families with CFC2. In
the first family, vertical transmission of the KRAS mutation occurred
from mother to son. The son had delayed psychomotor development and a
distinctive appearance, including curly hair, absent eyebrows, and broad
forehead. Echocardiogram was normal at age 3 years. His mother had a
similar physical appearance and also had high-arched palate, myopia, and
mitral valve prolapse. She had attended a school for children with
special needs. Both patients also showed signs of a peripheral
sensorimotor axonal neuropathy, more severe in the mother, who developed
Charcot arthropathy of the feet. PMP22 (601097) testing in the mother
was negative, but an additional cause of the neuropathy could not be
excluded. The proband of the second family, who had an unaffected
dizygotic twin, had a high birth weight, macrocephaly, and abnormal
craniofacial features, including proptosis, hypertelorism, downslanting
palpebral fissures, low-set ears, and short neck, suggestive of Noonan
syndrome. Reexamination at age 3.5 years showed coarser facial features
more consistent with CFC. She also had hypertrophy of the
interventricular myocardial septum, myocardial hypertrophy, and pulmonic
stenosis. She had mildly delayed development. Stark et al. (2012) cited
rare reports of peripheral neuropathy in CFC (DeRoos et al., 2007; Manci
et al., 2005), suggesting that it may be a feature of Ras-pathway
associated disorders. Overall, the report emphasized the expanding
phenotype of disorders due to germline KRAS mutations.

MOLECULAR GENETICS

Niihori et al. (2006) found the same heterozygous missense mutation in
the KRAS gene (D153V; 190070.0010) in patient 2 of Wieczorek et al.
(1997) and in another patient. They also identified a different KRAS
mutation (G60R; 190070.0009) in a third patient, and 8 mutations in BRAF
(e.g., 164757.0012) among 16 individuals.

Stark et al. (2012) reported 3 patients from 2 families with novel KRAS
mutations (Y71H, 190070.0021 and K147E, 190070.0022, respectively) and a
variable phenotype most consistent with a CFC-like syndrome. In the
first family, both a son and mother carried the Y71H mutation, which the
authors stated was the first documented vertically transmitted KRAS
mutation. The proband in the second family, who had a de novo K147E
mutation, was 1 of a female dizygotic twin pair; the other twin was
unaffected.

*FIELD* RF
1. DeRoos, S. T.; Ryan, M. M.; Ouvrier, R. A.: Peripheral neuropathy
in cardiofaciocutaneous syndrome. Pediat. Neurol. 36: 250-252, 2007.

2. Manci, E. A.; Martinez, J. E.; Horenstein, M. G.; Gardner, T.
M.; Ahmed, A.; Mancao, M. C.; Gremse, D. A.; Gardner, D. M.; Nimityongskul,
P.; Maertens, P.; Riddick, L.; Kavamura, M. I.: Cardiofaciocutaneous
syndrome (CFC) with congenital peripheral neuropathy and nonorganic
malnutrition: an autopsy study. Am. J. Med. Genet. 137A: 1-8, 2005.

3. Niihori, T.; Aoki, Y.; Narumi, Y.; Neri, G.; Cave, H.; Verloes,
A.; Okamoto, N.; Hennekam, R. C. M.; Gillessen-Kaesbach, G.; Wieczorek,
D.; Kavamura, M.I.; Kurosawa, K.; and 12 others: Germline KRAS
and BRAF mutations in cardio-facio-cutaneous syndrome. Nature Genet. 38:
294-296, 2006.

4. Stark, Z.; Gillessen-Kaesbach, G.; Ryan, M. M.; Cirstea, I. C.;
Gremer, L.; Ahmadian, M. R.; Savarirayan, R.; Zenker, M.: Two novel
germline KRAS mutations: expanding the molecular and clinical phenotype. Clin.
Genet. 81: 590-594, 2012.

5. Wieczorek, D.; Majewski, F.; Gillessen-Kaesbach, G.: Cardio-facio-cutaneous
(CFC) syndrome--a distinct entity? Report of three patients demonstrating
the diagnostic difficulties in delineation of CFC syndrome. Clin.
Genet. 52: 37-46, 1997.

*FIELD* CD
Anne M. Stumpf: 6/17/2013

*FIELD* ED
alopez: 06/18/2013

RBCC Red Blood Cell Collection

Full text data of KRAS