RBCC

Full text data of STK11

STK11 (LKB1, PJS) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Serine/threonine-protein kinase STK11; 2.7.11.1 (Liver kinase B1; LKB1; hLKB1; Renal carcinoma antigen NY-REN-19; Flags: Precursor)

UniProt Q15831
ID STK11_HUMAN Reviewed; 433 AA.
AC Q15831; B2RBX7; E7EW76;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Serine/threonine-protein kinase STK11;
DE EC=2.7.11.1;
DE AltName: Full=Liver kinase B1;
DE Short=LKB1;
DE Short=hLKB1;
DE AltName: Full=Renal carcinoma antigen NY-REN-19;
DE Flags: Precursor;
GN Name=STK11; Synonyms=LKB1, PJS;
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 [MRNA], AND INVOLVEMENT IN PJS.
RC TISSUE=Liver;
RX PubMed=9425897; DOI=10.1038/ng0198-38;
RA Jenne D.E., Reimann H., Nezu J., Friedl W., Loff S., Jeschke R.,
RA Mueller O., Back W., Zimmer M.;
RT "Peutz-Jeghers syndrome is caused by mutations in a novel serine
RT threonine kinase.";
RL Nat. Genet. 18:38-43(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9537235;
RA Bignell G.R., Barfoot R., Seal S., Collins N., Warren W.,
RA Stratton M.R.;
RT "Low frequency of somatic mutations in the LKB1/Peutz-Jeghers syndrome
RT gene in sporadic breast cancer.";
RL Cancer Res. 58:1384-1386(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [5]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, and Uterus;
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 [7]
RP IDENTIFICATION AS A RENAL CANCER ANTIGEN.
RC TISSUE=Renal cell carcinoma;
RX PubMed=10508479;
RX DOI=10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5;
RA Scanlan M.J., Gordan J.D., Williamson B., Stockert E., Bander N.H.,
RA Jongeneel C.V., Gure A.O., Jaeger D., Jaeger E., Knuth A., Chen Y.-T.,
RA Old L.J.;
RT "Antigens recognized by autologous antibody in patients with renal-
RT cell carcinoma.";
RL Int. J. Cancer 83:456-464(1999).
RN [8]
RP INVOLVEMENT IN LUNG CANCER.
RX PubMed=11212897; DOI=10.1023/A:1006442024874;
RA Sobottka S.B., Haase M., Fitze G., Hahn M., Schackert H.K.,
RA Schackert G.;
RT "Frequent loss of heterozygosity at the 19p13.3 locus without
RT LKB1/STK11 mutations in human carcinoma metastases to the brain.";
RL J. Neurooncol. 49:187-195(2000).
RN [9]
RP IDENTIFICATION IN A TERNARY COMPLEX COMPOSED OF SMAD4 AND STK11IP, AND
RP INTERACTION WITH SMAD4 AND STK11IP.
RX PubMed=11741830; DOI=10.1093/hmg/10.25.2869;
RA Smith D.P., Rayter S.I., Niederlander C., Spicer J., Jones C.M.,
RA Ashworth A.;
RT "LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers
RT syndrome kinase LKB1.";
RL Hum. Mol. Genet. 10:2869-2877(2001).
RN [10]
RP SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, FUNCTION, MUTAGENESIS OF
RP LYS-78 AND THR-189, AND PHOSPHORYLATION AT THR-189.
RX PubMed=11430832; DOI=10.1016/S1097-2765(01)00258-1;
RA Karuman P., Gozani O., Odze R.D., Zhou X.C., Zhu H., Shaw R.,
RA Brien T.P., Bozzuto C.D., Ooi D., Cantley L.C., Yuan J.;
RT "The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent
RT cell death.";
RL Mol. Cell 7:1307-1319(2001).
RN [11]
RP INVOLVEMENT IN LUNG CANCER.
RX PubMed=12097271;
RA Sanchez-Cespedes M., Parrella P., Esteller M., Nomoto S., Trink B.,
RA Engles J.M., Westra W.H., Herman J.G., Sidransky D.;
RT "Inactivation of LKB1/STK11 is a common event in adenocarcinomas of
RT the lung.";
RL Cancer Res. 62:3659-3662(2002).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH STRADA,
RP AUTOPHOSPHORYLATION AT THR-336 AND THR-363, AND CHARACTERIZATION OF
RP VARIANT SPORADIC CANCER TYR-176.
RX PubMed=12805220; DOI=10.1093/emboj/cdg292;
RA Baas A.F., Boudeau J., Sapkota G.P., Smit L., Medema R., Morrice N.A.,
RA Alessi D.R., Clevers H.C.;
RT "Activation of the tumour suppressor kinase LKB1 by the STE20-like
RT pseudokinase STRAD.";
RL EMBO J. 22:3062-3072(2003).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-194, IDENTIFICATION
RP IN A COMPLEX WITH STRADA AND CAB39, AND INTERACTION WITH STRADA;
RP STRADB; CAB39 AND CAB39L.
RX PubMed=14517248; DOI=10.1093/emboj/cdg490;
RA Boudeau J., Baas A.F., Deak M., Morrice N.A., Kieloch A.,
RA Schutkowski M., Prescott A.R., Clevers H.C., Alessi D.R.;
RT "MO25alpha/beta interact with STRADalpha/beta enhancing their ability
RT to bind, activate and localize LKB1 in the cytoplasm.";
RL EMBO J. 22:5102-5114(2003).
RN [14]
RP FUNCTION IN CELL POLARITY.
RX PubMed=15016379; DOI=10.1016/S0092-8674(04)00114-X;
RA Baas A.F., Kuipers J., van der Wel N.N., Batlle E., Koerten H.K.,
RA Peters P.J., Clevers H.C.;
RT "Complete polarization of single intestinal epithelial cells upon
RT activation of LKB1 by STRAD.";
RL Cell 116:457-466(2004).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-194.
RX PubMed=14976552; DOI=10.1038/sj.emboj.7600110;
RA Lizcano J.M., Goeransson O., Toth R., Deak M., Morrice N.A.,
RA Boudeau J., Hawley S.A., Udd L., Maekelae T.P., Hardie D.G.,
RA Alessi D.R.;
RT "LKB1 is a master kinase that activates 13 kinases of the AMPK
RT subfamily, including MARK/PAR-1.";
RL EMBO J. 23:833-843(2004).
RN [16]
RP INVOLVEMENT IN LUNG CANCER.
RX PubMed=15021901; DOI=10.1038/sj.onc.1207502;
RA Carretero J., Medina P.P., Pio R., Montuenga L.M.,
RA Sanchez-Cespedes M.;
RT "Novel and natural knockout lung cancer cell lines for the LKB1/STK11
RT tumor suppressor gene.";
RL Oncogene 23:4037-4040(2004).
RN [17]
RP FUNCTION.
RX PubMed=15733851; DOI=10.1016/j.febslet.2005.01.042;
RA Jaleel M., McBride A., Lizcano J.M., Deak M., Toth R., Morrice N.A.,
RA Alessi D.R.;
RT "Identification of the sucrose non-fermenting related kinase SNRK, as
RT a novel LKB1 substrate.";
RL FEBS Lett. 579:1417-1423(2005).
RN [18]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH TP53.
RX PubMed=17108107; DOI=10.1158/0008-5472.CAN-06-0999;
RA Zeng P.Y., Berger S.L.;
RT "LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate
RT transcriptional activation.";
RL Cancer Res. 66:10701-10708(2006).
RN [19]
RP INTERACTION WITH WDR6.
RX PubMed=17216128; DOI=10.1007/s11010-006-9402-5;
RA Xie X., Wang Z., Chen Y.;
RT "Association of LKB1 with a WD-repeat protein WDR6 is implicated in
RT cell growth arrest and p27(Kip1) induction.";
RL Mol. Cell. Biochem. 301:115-122(2007).
RN [20]
RP INVOLVEMENT IN LUNG CANCER.
RX PubMed=17711506; DOI=10.1111/j.1349-7006.2007.00585.x;
RA Onozato R., Kosaka T., Achiwa H., Kuwano H., Takahashi T., Yatabe Y.,
RA Mitsudomi T.;
RT "LKB1 gene mutations in Japanese lung cancer patients.";
RL Cancer Sci. 98:1747-1751(2007).
RN [21]
RP INVOLVEMENT IN LUNG CANCER.
RX PubMed=17676035; DOI=10.1038/nature06030;
RA Ji H., Ramsey M.R., Hayes D.N., Fan C., McNamara K., Kozlowski P.,
RA Torrice C., Wu M.C., Shimamura T., Perera S.A., Liang M.C., Cai D.,
RA Naumov G.N., Bao L., Contreras C.M., Li D., Chen L., Krishnamurthy J.,
RA Koivunen J., Chirieac L.R., Padera R.F., Bronson R.T., Lindeman N.I.,
RA Christiani D.C., Lin X., Shapiro G.I., Janne P.A., Johnson B.E.,
RA Meyerson M., Kwiatkowski D.J., Castrillon D.H., Bardeesy N.,
RA Sharpless N.E., Wong K.K.;
RT "LKB1 modulates lung cancer differentiation and metastasis.";
RL Nature 448:807-810(2007).
RN [22]
RP INVOLVEMENT IN LUNG CANCER.
RX PubMed=17384680; DOI=10.1038/sj.onc.1210418;
RA Matsumoto S., Iwakawa R., Takahashi K., Kohno T., Nakanishi Y.,
RA Matsuno Y., Suzuki K., Nakamoto M., Shimizu E., Minna J.D., Yokota J.;
RT "Prevalence and specificity of LKB1 genetic alterations in lung
RT cancers.";
RL Oncogene 26:5911-5918(2007).
RN [23]
RP INVOLVEMENT IN LUNG CANCER.
RX PubMed=18594528; DOI=10.1038/sj.bjc.6604469;
RA Koivunen J.P., Kim J., Lee J., Rogers A.M., Park J.O., Zhao X.,
RA Naoki K., Okamoto I., Nakagawa K., Yeap B.Y., Meyerson M., Wong K.K.,
RA Richards W.G., Sugarbaker D.J., Johnson B.E., Janne P.A.;
RT "Mutations in the LKB1 tumour suppressor are frequently detected in
RT tumours from Caucasian but not Asian lung cancer patients.";
RL Br. J. Cancer 99:245-252(2008).
RN [24]
RP ALTERNATIVE SPLICING (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION,
RP PHOSPHORYLATION AT SER-428, AND MUTAGENESIS OF SER-428.
RX PubMed=18854309; DOI=10.1074/jbc.M806153200;
RA Denison F.C., Hiscock N.J., Carling D., Woods A.;
RT "Characterization of an alternative splice variant of LKB1.";
RL J. Biol. Chem. 284:67-76(2009).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [26]
RP INVOLVEMENT IN LUNG CANCER.
RX PubMed=20559149; DOI=10.1097/JTO.0b013e3181e05016;
RA Gao B., Sun Y., Zhang J., Ren Y., Fang R., Han X., Shen L., Liu X.Y.,
RA Pao W., Chen H., Ji H.;
RT "Spectrum of LKB1, EGFR, and KRAS mutations in Chinese lung
RT adenocarcinomas.";
RL J. Thorac. Oncol. 5:1130-1135(2010).
RN [27]
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 [28]
RP FUNCTION.
RX PubMed=21317932; DOI=10.1038/onc.2011.19;
RA Hou X., Liu J.E., Liu W., Liu C.Y., Liu Z.Y., Sun Z.Y.;
RT "A new role of NUAK1: directly phosphorylating p53 and regulating cell
RT proliferation.";
RL Oncogene 30:2933-2942(2011).
RN [29]
RP REVIEW ON FUNCTION.
RX PubMed=21396365; DOI=10.1016/j.febslet.2011.03.010;
RA Alexander A., Walker C.L.;
RT "The role of LKB1 and AMPK in cellular responses to stress and
RT damage.";
RL FEBS Lett. 585:952-957(2011).
RN [30]
RP REVIEW ON INVOLVEMENT IN LUNG CANCER.
RX PubMed=21380642; DOI=10.1007/s13238-011-1021-6;
RA Gao Y., Ge G., Ji H.;
RT "LKB1 in lung cancerigenesis: a serine/threonine kinase as tumor
RT suppressor.";
RL Protein Cell 2:99-107(2011).
RN [31]
RP ENZYME REGULATION, INTERACTION WITH NR4A1, AND SUBCELLULAR LOCATION.
RX PubMed=22983157; DOI=10.1038/nchembio.1069;
RA Zhan Y.Y., Chen Y., Zhang Q., Zhuang J.J., Tian M., Chen H.Z.,
RA Zhang L.R., Zhang H.K., He J.P., Wang W.J., Wu R., Wang Y., Shi C.,
RA Yang K., Li A.Z., Xin Y.Z., Li T.Y., Yang J.Y., Zheng Z.H., Yu C.D.,
RA Lin S.C., Chang C., Huang P.Q., Lin T., Wu Q.;
RT "The orphan nuclear receptor Nur77 regulates LKB1 localization and
RT activates AMPK.";
RL Nat. Chem. Biol. 8:897-904(2012).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 43-347 IN COMPLEX WITH
RP STRADA AND CAB39, ENZYME REGULATION, CHARACTERIZATION OF VARIANTS
RP SPORADIC CANCER MET-66; GLY-86; ARG-123; SER-157; ASP-163; PRO-170;
RP SER-171; ARG-174; TYR-176; ASN-177; GLU-181; GLN-199; THR-205;
RP PHE-216; VAL-223; PRO-230; PRO-232; ARG-245; PRO-250; HIS-272;
RP TYR-277; GLN-285 AND SER-315, AND MUTAGENESIS OF ARG-74; ASP-194 AND
RP PHE-204.
RX PubMed=19892943; DOI=10.1126/science.1178377;
RA Zeqiraj E., Filippi B.M., Deak M., Alessi D.R., van Aalten D.M.;
RT "Structure of the LKB1-STRAD-MO25 complex reveals an allosteric
RT mechanism of kinase activation.";
RL Science 326:1707-1711(2009).
RN [33]
RP VARIANT TGCT ASP-163.
RX PubMed=9605748;
RA Avizienyte E., Roth S., Loukola A., Hemminki A., Lothe R.A.,
RA Stenwig A.E., Fossaa S.D., Salovaara R., Aaltonen L.A.;
RT "Somatic mutations in LKB1 are rare in sporadic colorectal and
RT testicular tumors.";
RL Cancer Res. 58:2087-2090(1998).
RN [34]
RP VARIANTS COLORECTAL CANCER SER-171; LYS-199; ASN-208; ASP-215; LEU-354
RP AND MET-367.
RX PubMed=9731485;
RA Dong S.M., Kim K.M., Kim S.Y., Shin M.S., Na E.Y., Lee S.H.,
RA Park W.S., Yoo N.J., Jang J.J., Yoon C.Y., Kim J.W., Kim S.Y.,
RA Yang Y.M., Kim S.H., Kim C.S., Lee J.Y.;
RT "Frequent somatic mutations in serine/threonine kinase 11/Peutz-
RT Jeghers syndrome gene in left-sided colon cancer.";
RL Cancer Res. 58:3787-3790(1998).
RN [35]
RP VARIANT COLORECTAL CANCER HIS-314.
RX PubMed=9809980;
RA Resta N., Simone C., Mareni C., Montera M., Gentile M., Susca F.,
RA Gristina R., Pozzi S., Bertario L., Bufo P., Carlomagno N.,
RA Ingrosso M., Rossini F.P., Tenconi R., Guanti G.;
RT "STK11 mutations in Peutz-Jeghers syndrome and sporadic colon
RT cancer.";
RL Cancer Res. 58:4799-4801(1998).
RN [36]
RP VARIANT PJS ASN-247 DEL.
RX PubMed=9760200; DOI=10.1007/s004390050801;
RA Nakagawa H., Koyama K., Miyoshi Y., Ando H., Baba S., Watatani M.,
RA Yasutomi M., Matsuura N., Monden M., Nakamura Y.;
RT "Nine novel germline mutations of STK11 in ten families with Peutz-
RT Jeghers syndrome.";
RL Hum. Genet. 103:168-172(1998).
RN [37]
RP VARIANT GASTRIC CARCINOMA LEU-324.
RX PubMed=9683800;
RA Park W.S., Moon Y.W., Yang Y.M., Kim Y.S., Kim Y.D., Fuller B.G.,
RA Vortmeyer A.O., Fogt F., Lubensky I.A., Zhuang Z.;
RT "Mutations of the STK11 gene in sporadic gastric carcinoma.";
RL Int. J. Oncol. 13:601-604(1998).
RN [38]
RP VARIANTS PJS PRO-67 AND 303-ILE--GLN-306 DELINS ASN.
RX PubMed=9428765; DOI=10.1038/34432;
RA Hemminki A., Markie D., Tomlinson I., Avizienyte E., Roth S.,
RA Loukola A., Bignell G., Warren W., Aminoff M., Hoeglund P.,
RA Jaervinen H., Kristo P., Pelin K., Ridanpaeae M., Salovaara R.,
RA Toro T., Bodmer W., Olschwang S., Olsen A.S., Stratton M.R.,
RA de la Chapelle A., Aaltonen L.A.;
RT "A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.";
RL Nature 391:184-187(1998).
RN [39]
RP VARIANT LUNG CANCER VAL-194.
RX PubMed=10079245; DOI=10.1016/S0002-9440(10)65314-X;
RA Avizienyte E., Loukola A., Roth S., Hemminki A., Tarkkanen M.,
RA Salovaara R., Arola J., Butzow R., Husgafvel-Pursiainen K.,
RA Kokkola A., Jarvinen H., Aaltonen L.A.;
RT "LKB1 somatic mutations in sporadic cancers.";
RL Am. J. Pathol. 154:677-681(1999).
RN [40]
RP VARIANTS PJS 162-ASN--MET-164; ASN-194 AND LYS-297.
RX PubMed=10408777;
RX DOI=10.1002/(SICI)1098-1004(1999)13:6<476::AID-HUMU7>3.3.CO;2-U;
RA Westerman A.M., Entius M.M., Boor P.P.C., Koole R., de Baar E.,
RA Offerhaus G.J.A., Lubinski J., Lindhout D., Halley D.J.J.,
RA de Rooij F.W.M., Wilson J.H.P.;
RT "Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers
RT families.";
RL Hum. Mutat. 13:476-481(1999).
RN [41]
RP CHARACTERIZATION OF VARIANT TGCT ASP-163.
RX PubMed=9887330; DOI=10.1093/hmg/8.1.45;
RA Ylikorkala A., Avizienyte E., Tomlinson I.P., Tiainen M., Roth S.,
RA Loukola A., Hemminki A., Johansson M., Sistonen P., Markie D.,
RA Neale K., Phillips R., Zauber P., Twama T., Sampson J., Jaervinen H.,
RA Maekelae T.P., Aaltonen L.A.;
RT "Mutations and impaired function of LKB1 in familial and non-familial
RT Peutz-Jeghers syndrome and a sporadic testicular cancer.";
RL Hum. Mol. Genet. 8:45-51(1999).
RN [42]
RP VARIANT OVARIAN CARCINOMA LEU-281.
RX PubMed=10429654;
RA Nishioka Y., Kobayashi K., Sagae S., Sugimura M., Ishioka S.,
RA Nagata M., Terasawa K., Tokino T., Kudo R.;
RT "Mutational analysis of STK11 gene in ovarian carcinomas.";
RL Jpn. J. Cancer Res. 90:629-632(1999).
RN [43]
RP VARIANTS MELANOMA ASP-49 AND ARG-135.
RX PubMed=10201537; DOI=10.1046/j.1523-1747.1999.00551.x;
RA Rowan A., Bataille V., MacKie R., Healy E., Bicknell D., Bodmer W.,
RA Tomlinson I.;
RT "Somatic mutations in the Peutz-Jeghers (LKB1/STKII) gene in sporadic
RT malignant melanomas.";
RL J. Invest. Dermatol. 112:509-511(1999).
RN [44]
RP VARIANT MELANOMA TYR-194.
RX PubMed=10208439; DOI=10.1038/sj.onc.1202486;
RA Guldberg P., thor Straten P., Ahrenkiel V., Seremet T., Kirkin A.F.,
RA Zeuthen J.;
RT "Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in
RT malignant melanoma.";
RL Oncogene 18:1777-1780(1999).
RN [45]
RP VARIANTS PJS CYS-239 AND SER-315.
RX PubMed=12372054; DOI=10.1034/j.1399-0004.2002.620405.x;
RA Scott R.J., Crooks R., Meldrum C.J., Thomas L., Smith C.J.A.,
RA Mowat D., McPhillips M., Spigelman A.D.;
RT "Mutation analysis of the STK11/LKB1 gene and clinical characteristics
RT of an Australian series of Peutz-Jeghers syndrome patients.";
RL Clin. Genet. 62:282-287(2002).
RN [46]
RP VARIANTS CERVICAL CANCER LYS-14; PRO-160 AND LEU-231, AND VARIANT
RP CERVICAL CARCINOMA MET-66.
RX PubMed=12533684;
RA Kuragaki C., Enomoto T., Ueno Y., Sun H., Fujita M., Nakashima R.,
RA Ueda Y., Wada H., Murata Y., Toki T., Konishi I., Fujii S.;
RT "Mutations in the STK11 gene characterize minimal deviation
RT adenocarcinoma of the uterine cervix.";
RL Lab. Invest. 83:35-45(2003).
RN [47]
RP VARIANT [LARGE SCALE ANALYSIS] LYS-87.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [48]
RP VARIANT PJS GLY-16.
RX PubMed=21411391; DOI=10.1016/j.clinre.2010.11.008;
RA Liu L., Du X., Nie J.;
RT "A novel de novo mutation in LKB1 gene in a Chinese Peutz Jeghers
RT syndrome patient significantly diminished p53 activity.";
RL Clin. Res. Hepatol. Gastroenterol. 35:221-226(2011).
CC -!- FUNCTION: Tumor suppressor serine/threonine-protein kinase that
CC controls the activity of AMP-activated protein kinase (AMPK)
CC family members, thereby playing a role in various processes such
CC as cell metabolism, cell polarity, apoptosis and DNA damage
CC response. Acts by phosphorylating the T-loop of AMPK family
CC proteins, leading to promote their activity: phosphorylates
CC PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1,
CC NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates
CC non-AMPK family proteins such as STRADA and possibly p53/TP53.
CC Acts as a key upstream regulator of AMPK by mediating
CC phosphorylation and activation of AMPK catalytic subunits PRKAA1
CC and PRKAA2: it thereby regulates inhibition of signaling pathways
CC that promote cell growth and proliferation when energy levels are
CC low, glucose homeostasis in liver, activation of autophagy when
CC cells undergo nutrient deprivation, B-cell differentiation in the
CC germinal center in response to DNA damage. Also acts as a
CC regulator of cellular polarity by remodeling the actin
CC cytoskeleton. Required for cortical neurons polarization by
CC mediating phosphorylation and activation of BRSK1 and BRSK2,
CC leading to axon initiation and specification. Involved in DNA
CC damage response: interacts with p53/TP53 and recruited to the
CC CDKN1A/WAF1 promoter to participate in transcription activation.
CC Able to phosphorylate p53/TP53; the relevance of such result in
CC vivo is however unclear and phosphorylation may be indirect and
CC mediated by downstream STK11/LKB1 kinase NUAK1 Also acts as a
CC mediator p53/TP53-dependent apoptosis via interaction with
CC p53/TP53: translocates to mitochondrion during apoptosis and
CC regulates p53/TP53-dependent apoptosis pathways.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium or Manganese.
CC -!- ENZYME REGULATION: Activated by forming a complex with STRAD
CC (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or
CC CAB39L/MO25beta): STRADA (or STRADB)-binding promotes a
CC conformational change of STK11/LKB1 in an active conformation,
CC which is stabilized by CAB39/MO25alpha (or CAB39L/MO25beta)
CC interacting with the STK11/LKB1 activation loop. Sequestration in
CC the nucleus by NR4A1 prevents it from phosphorylating and
CC activating cytoplasmic AMPK.
CC -!- SUBUNIT: Catalytic component of a trimeric complex composed of
CC STK11/LKB1, STRAD (STRADA or STRADB) and CAB39/MO25
CC (CAB39/MO25alpha or CAB39L/MO25beta): the complex tethers
CC STK11/LKB1 in the cytoplasm and stimulates its catalytic activity.
CC Found in a ternary complex composed of SMAD4, STK11/LKB1 and
CC STK11IP. Interacts with p53/TP53, SMAD4, STK11IP and WDR6.
CC Interacts with NR4A1.
CC -!- INTERACTION:
CC Q9Y376:CAB39; NbExp=4; IntAct=EBI-306838, EBI-306905;
CC P08238:HSP90AB1; NbExp=3; IntAct=EBI-306838, EBI-352572;
CC Q96L34:MARK4; NbExp=2; IntAct=EBI-306838, EBI-302319;
CC Q7RTN6:STRADA; NbExp=9; IntAct=EBI-306838, EBI-1109114;
CC Q9C0K7:STRADB; NbExp=6; IntAct=EBI-306838, EBI-306893;
CC Q8NFZ5:TNIP2; NbExp=5; IntAct=EBI-306838, EBI-359372;
CC Q9NNW5:WDR6; NbExp=3; IntAct=EBI-306838, EBI-1568315;
CC P63104:YWHAZ; NbExp=6; IntAct=EBI-306838, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Membrane (By
CC similarity). Mitochondrion. Note=A small fraction localizes at
CC membranes (By similarity). Relocates to the cytoplasm when bound
CC to STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or
CC CAB39L/MO25beta). Translocates to mitochondrion during apoptosis.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=LKB1(L);
CC IsoId=Q15831-1; Sequence=Displayed;
CC Name=2; Synonyms=LKB1(S);
CC IsoId=Q15831-2; Sequence=VSP_041746;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Strongest expression
CC in testis and fetal liver.
CC -!- PTM: Phosphorylated by ATM at Thr-363 following ionizing
CC radiations (IR). Phosphorylation at Ser-428 by RPS6KA1 and/or some
CC PKA is required to inhibit cell growth. Phosphorylation at Ser-428
CC is also required during neuronal polarization to mediate
CC phosphorylation of BRSK1 and BRSK2 (By similarity).
CC -!- DISEASE: Peutz-Jeghers syndrome (PJS) [MIM:175200]: An autosomal
CC dominant disorder characterized by melanocytic macules of the
CC lips, multiple gastrointestinal hamartomatous polyps and an
CC increased risk for various neoplasms, including gastrointestinal
CC cancer. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Testicular germ cell tumor (TGCT) [MIM:273300]: A common
CC malignancy in males representing 95% of all testicular neoplasms.
CC TGCTs have various pathologic subtypes including: unclassified
CC intratubular germ cell neoplasia, seminoma (including cases with
CC syncytiotrophoblastic cells), spermatocytic seminoma, embryonal
CC carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. Note=The
CC gene represented in this entry may be involved in disease
CC pathogenesis.
CC -!- DISEASE: Note=Defects in STK11 are associated with some sporadic
CC cancers, especially lung cancers. Frequently mutated and
CC inactivated in non-small cell lung cancer (NSCLC). Defects promote
CC lung cancerigenesis process, especially lung cancer progression
CC and metastasis. Confers lung adenocarcinoma the ability to trans-
CC differentiate into squamous cell carcinoma. Also able to promotes
CC lung cancer metastasis, via both cancer-cell autonomous and non-
CC cancer-cell autonomous mechanisms.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
CC Ser/Thr protein kinase family. LKB1 subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/STK11ID292.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/STK11";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=PJS entry;
CC URL="http://en.wikipedia.org/wiki/PJS";
CC -----------------------------------------------------------------------
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DR EMBL; U63333; AAB05809.1; -; mRNA.
DR EMBL; AF035625; AAC39527.1; -; mRNA.
DR EMBL; AF032984; AAB97833.1; -; Genomic_DNA.
DR EMBL; AF055327; AAC15742.1; -; Genomic_DNA.
DR EMBL; AF055320; AAC15742.1; JOINED; Genomic_DNA.
DR EMBL; AF055321; AAC15742.1; JOINED; Genomic_DNA.
DR EMBL; AF055322; AAC15742.1; JOINED; Genomic_DNA.
DR EMBL; AF055323; AAC15742.1; JOINED; Genomic_DNA.
DR EMBL; AF055324; AAC15742.1; JOINED; Genomic_DNA.
DR EMBL; AF055325; AAC15742.1; JOINED; Genomic_DNA.
DR EMBL; AF055326; AAC15742.1; JOINED; Genomic_DNA.
DR EMBL; AK314858; BAG37374.1; -; mRNA.
DR EMBL; AC011544; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC004221; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69540.1; -; Genomic_DNA.
DR EMBL; BC007981; AAH07981.1; -; mRNA.
DR EMBL; BC019334; AAH19334.1; -; mRNA.
DR RefSeq; NP_000446.1; NM_000455.4.
DR RefSeq; XP_005259675.1; XM_005259618.1.
DR UniGene; Hs.515005; -.
DR PDB; 2WTK; X-ray; 2.65 A; C/F=43-347.
DR PDBsum; 2WTK; -.
DR ProteinModelPortal; Q15831; -.
DR SMR; Q15831; 22-369.
DR DIP; DIP-31317N; -.
DR IntAct; Q15831; 37.
DR MINT; MINT-204048; -.
DR STRING; 9606.ENSP00000324856; -.
DR BindingDB; Q15831; -.
DR ChEMBL; CHEMBL5606; -.
DR GuidetoPHARMACOLOGY; 2212; -.
DR PhosphoSite; Q15831; -.
DR DMDM; 3024670; -.
DR PaxDb; Q15831; -.
DR PRIDE; Q15831; -.
DR DNASU; 6794; -.
DR Ensembl; ENST00000326873; ENSP00000324856; ENSG00000118046.
DR GeneID; 6794; -.
DR KEGG; hsa:6794; -.
DR UCSC; uc002lrl.1; human.
DR CTD; 6794; -.
DR GeneCards; GC19P001205; -.
DR HGNC; HGNC:11389; STK11.
DR HPA; CAB016231; -.
DR HPA; CAB022105; -.
DR HPA; HPA017254; -.
DR MIM; 175200; phenotype.
DR MIM; 273300; phenotype.
DR MIM; 602216; gene.
DR neXtProt; NX_Q15831; -.
DR Orphanet; 2869; Peutz-Jeghers syndrome.
DR PharmGKB; PA36198; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000007002; -.
DR HOVERGEN; HBG054467; -.
DR InParanoid; Q15831; -.
DR KO; K07298; -.
DR OMA; KKHPPSE; -.
DR OrthoDB; EOG7F7W92; -.
DR BRENDA; 2.7.11.1; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR SignaLink; Q15831; -.
DR ChiTaRS; STK11; human.
DR EvolutionaryTrace; Q15831; -.
DR GeneWiki; STK11; -.
DR GenomeRNAi; 6794; -.
DR NextBio; 26541; -.
DR PRO; PR:Q15831; -.
DR ArrayExpress; Q15831; -.
DR Bgee; Q15831; -.
DR CleanEx; HS_STK11; -.
DR Genevestigator; Q15831; -.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0002039; F:p53 binding; IDA:UniProtKB.
DR GO; GO:0030295; F:protein kinase activator activity; IDA:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0032147; P:activation of protein kinase activity; IDA:MGI.
DR GO; GO:0043276; P:anoikis; IMP:BHF-UCL.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0007409; P:axonogenesis; IEA:Ensembl.
DR GO; GO:0060070; P:canonical Wnt receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0007050; P:cell cycle arrest; IDA:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0030010; P:establishment of cell polarity; ISS:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0051645; P:Golgi localization; IEA:Ensembl.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; IDA:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IMP:UniProtKB.
DR GO; GO:0060770; P:negative regulation of epithelial cell proliferation involved in prostate gland development; IEA:Ensembl.
DR GO; GO:0050772; P:positive regulation of axonogenesis; IEA:Ensembl.
DR GO; GO:0045722; P:positive regulation of gluconeogenesis; IEA:Ensembl.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0042304; P:regulation of fatty acid biosynthetic process; TAS:Reactome.
DR GO; GO:0051896; P:regulation of protein kinase B signaling cascade; IEA:Ensembl.
DR GO; GO:0030111; P:regulation of Wnt receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0033762; P:response to glucagon stimulus; IEA:Ensembl.
DR GO; GO:0010212; P:response to ionizing radiation; ISS:UniProtKB.
DR GO; GO:0033993; P:response to lipid; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0007286; P:spermatid development; IEA:Ensembl.
DR GO; GO:0001894; P:tissue homeostasis; IEA:Ensembl.
DR GO; GO:0001944; P:vasculature development; ISS:UniProtKB.
DR InterPro; IPR020636; Ca/CaM-dep_Ca-dep_prot_Kinase.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR24347; PTHR24347; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; ATP-binding; Autophagy;
KW Cell cycle; Complete proteome; Cytoplasm; Disease mutation;
KW DNA damage; Kinase; Lipoprotein; Magnesium; Manganese; Membrane;
KW Metal-binding; Methylation; Mitochondrion; Nucleotide-binding;
KW Nucleus; Palmitate; Phosphoprotein; Polymorphism; Prenylation;
KW Reference proteome; Serine/threonine-protein kinase; Transferase;
KW Tumor suppressor.
FT CHAIN 1 430 Serine/threonine-protein kinase STK11.
FT /FTId=PRO_0000086699.
FT PROPEP 431 433 Removed in mature form (By similarity).
FT /FTId=PRO_0000422300.
FT DOMAIN 49 309 Protein kinase.
FT NP_BIND 55 63 ATP (By similarity).
FT ACT_SITE 176 176 Proton acceptor.
FT BINDING 78 78 ATP (Probable).
FT MOD_RES 31 31 Phosphoserine (By similarity).
FT MOD_RES 189 189 Phosphothreonine; by autocatalysis.
FT MOD_RES 325 325 Phosphoserine (By similarity).
FT MOD_RES 336 336 Phosphothreonine; by autocatalysis.
FT MOD_RES 363 363 Phosphothreonine; by ATM and
FT autocatalysis.
FT MOD_RES 428 428 Phosphoserine; by PKA and RPS6KA1.
FT MOD_RES 430 430 Cysteine methyl ester (By similarity).
FT LIPID 418 418 S-palmitoyl cysteine (By similarity).
FT LIPID 430 430 S-farnesyl cysteine (By similarity).
FT VAR_SEQ 371 433 QVPEEEASHNGQRRGLPKAVCMNGTEAAQLSTKSRAEGRAP
FT NPARKACSASSKIRRLSACKQQ -> GEEASEAGLRAERGL
FT QKSEGSDLSGEEASRPAPQ (in isoform 2).
FT /FTId=VSP_041746.
FT VARIANT 14 14 E -> K (in cervical cancer; somatic
FT mutation).
FT /FTId=VAR_065627.
FT VARIANT 16 16 E -> G (in PJS).
FT /FTId=VAR_065628.
FT VARIANT 49 49 Y -> D (in melanoma; sporadic malignant;
FT somatic mutation).
FT /FTId=VAR_033138.
FT VARIANT 66 66 V -> M (in cervical carcinoma; somatic
FT mutation).
FT /FTId=VAR_065629.
FT VARIANT 67 67 L -> P (in PJS).
FT /FTId=VAR_006202.
FT VARIANT 86 86 R -> G (in sporadic cancer; somatic
FT mutation; no effect on kinase activity
FT nor in heterotrimeric complex assembly
FT with STRADA and CAB39).
FT /FTId=VAR_065630.
FT VARIANT 87 87 R -> K (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_041139.
FT VARIANT 123 123 Q -> R (in sporadic cancer; somatic
FT mutation; no effect on kinase activity
FT nor in heterotrimeric complex assembly
FT with STRADA and CAB39).
FT /FTId=VAR_065631.
FT VARIANT 135 135 G -> R (in melanoma; sporadic malignant;
FT somatic mutation).
FT /FTId=VAR_033139.
FT VARIANT 157 157 F -> S (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065632.
FT VARIANT 160 160 L -> P (in cervical cancer; somatic
FT mutation).
FT /FTId=VAR_065633.
FT VARIANT 162 164 DGL -> NDM (in PJS).
FT /FTId=VAR_007920.
FT VARIANT 163 163 G -> D (in TGCT; a tumor with seminoma
FT and teratoma components; associated with
FT severely impaired but detectable kinase
FT activity; somatic mutation; impairs
FT heterotrimeric complex assembly with
FT STRADA and CAB39).
FT /FTId=VAR_033140.
FT VARIANT 170 170 Q -> P (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065634.
FT VARIANT 171 171 G -> S (in colorectal cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065635.
FT VARIANT 174 174 H -> R (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065636.
FT VARIANT 176 176 D -> Y (in sporadic cancer; somatic
FT mutation; Loss of kinase activity).
FT /FTId=VAR_065637.
FT VARIANT 177 177 I -> N (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065638.
FT VARIANT 181 181 N -> E (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39; requires
FT 2 nucleotide substitutions).
FT /FTId=VAR_065639.
FT VARIANT 194 194 D -> N (in PJS).
FT /FTId=VAR_007921.
FT VARIANT 194 194 D -> V (in lung cancer; somatic
FT mutation).
FT /FTId=VAR_065640.
FT VARIANT 194 194 D -> Y (in melanoma; sporadic malignant;
FT somatic mutation).
FT /FTId=VAR_033141.
FT VARIANT 199 199 E -> K (in colorectal cancer; somatic
FT mutation; impaired kinase activity).
FT /FTId=VAR_065641.
FT VARIANT 199 199 E -> Q (in sporadic cancer; somatic
FT mutation; does not affect kinase
FT activity).
FT /FTId=VAR_065642.
FT VARIANT 205 205 A -> T (in sporadic cancer; somatic
FT mutation; no effect heterotrimeric
FT complex assembly with STRADA and CAB39).
FT /FTId=VAR_065643.
FT VARIANT 208 208 D -> N (in colorectal cancer; somatic
FT mutation; no effect heterotrimeric
FT complex assembly with STRADA and CAB39).
FT /FTId=VAR_065644.
FT VARIANT 215 215 G -> D (in colorectal cancer; somatic
FT mutation).
FT /FTId=VAR_065645.
FT VARIANT 216 216 S -> F (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065646.
FT VARIANT 223 223 E -> V (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065647.
FT VARIANT 230 230 T -> P (in sporadic cancer; somatic
FT mutation; no effect heterotrimeric
FT complex assembly with STRADA and CAB39).
FT /FTId=VAR_065648.
FT VARIANT 231 231 F -> L (in cervical cancer; somatic
FT mutation).
FT /FTId=VAR_065649.
FT VARIANT 232 232 S -> P (in sporadic cancer; somatic
FT mutation; no effect heterotrimeric
FT complex assembly with STRADA and CAB39).
FT /FTId=VAR_065650.
FT VARIANT 239 239 W -> C (in PJS; late onset suggests
FT reduced penetrance).
FT /FTId=VAR_033142.
FT VARIANT 245 245 L -> R (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065651.
FT VARIANT 247 247 Missing (in PJS).
FT /FTId=VAR_006203.
FT VARIANT 250 250 T -> P (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065652.
FT VARIANT 272 272 Y -> H (in sporadic cancer; somatic
FT mutation; no effect on kinase activity
FT nor in heterotrimeric complex assembly
FT with STRADA and CAB39).
FT /FTId=VAR_065653.
FT VARIANT 277 277 D -> Y (in sporadic cancer; somatic
FT mutation; no effect on kinase activity
FT nor in heterotrimeric complex assembly
FT with STRADA and CAB39).
FT /FTId=VAR_065654.
FT VARIANT 281 281 P -> L (in ovarian carcinoma; somatic
FT mutation).
FT /FTId=VAR_065655.
FT VARIANT 285 285 L -> Q (in sporadic cancer; somatic
FT mutation; impairs heterotrimeric complex
FT assembly with STRADA and CAB39).
FT /FTId=VAR_065656.
FT VARIANT 297 297 R -> K (in PJS).
FT /FTId=VAR_007922.
FT VARIANT 303 306 IRQH -> N (in PJS).
FT /FTId=VAR_033143.
FT VARIANT 314 314 P -> H (in colorectal cancer; no effect
FT heterotrimeric complex assembly with
FT STRADA and CAB39).
FT /FTId=VAR_065657.
FT VARIANT 315 315 P -> S (in PJS; pathogenicity uncertain;
FT no effect heterotrimeric complex assembly
FT with STRADA and CAB39).
FT /FTId=VAR_033144.
FT VARIANT 324 324 P -> L (in gastric carcinoma; no effect
FT heterotrimeric complex assembly with
FT STRADA and CAB39).
FT /FTId=VAR_065658.
FT VARIANT 354 354 F -> L (in colorectal cancer; somatic
FT mutation).
FT /FTId=VAR_065659.
FT VARIANT 367 367 T -> M (in colorectal cancer; somatic
FT mutation).
FT /FTId=VAR_065660.
FT MUTAGEN 74 74 R->A: Impaired formation of a
FT heterotrimeric complex with STRADA and
FT CAB39; when associated with A-204.
FT MUTAGEN 78 78 K->M: Loss of kinase activity, leading to
FT reduced autophosphorylation and acting as
FT a dominant-negative mutant.
FT MUTAGEN 189 189 T->A: Reduced phosphorylation.
FT MUTAGEN 194 194 D->A: Loss of kinase activity.
FT MUTAGEN 204 204 F->A: No effect. Impaired formation of a
FT heterotrimeric complex with STRADA and
FT CAB39; when associated with A-74.
FT MUTAGEN 428 428 S->A,E: No effect on kinase activity.
FT STRAND 54 57
FT STRAND 62 68
FT TURN 69 71
FT STRAND 74 80
FT HELIX 82 87
FT HELIX 91 102
FT STRAND 113 118
FT STRAND 125 130
FT STRAND 133 135
FT HELIX 136 142
FT HELIX 150 169
FT HELIX 179 181
FT STRAND 182 184
FT STRAND 190 192
FT HELIX 217 219
FT HELIX 222 225
FT STRAND 231 233
FT HELIX 234 250
FT HELIX 260 269
FT STRAND 276 278
FT HELIX 280 289
FT TURN 294 296
FT HELIX 300 305
FT HELIX 307 310
FT HELIX 339 341
SQ SEQUENCE 433 AA; 48636 MW; 6DF4C37AB7A89569 CRC64;
MEVVDPQQLG MFTEGELMSV GMDTFIHRID STEVIYQPRR KRAKLIGKYL MGDLLGEGSY
GKVKEVLDSE TLCRRAVKIL KKKKLRRIPN GEANVKKEIQ LLRRLRHKNV IQLVDVLYNE
EKQKMYMVME YCVCGMQEML DSVPEKRFPV CQAHGYFCQL IDGLEYLHSQ GIVHKDIKPG
NLLLTTGGTL KISDLGVAEA LHPFAADDTC RTSQGSPAFQ PPEIANGLDT FSGFKVDIWS
AGVTLYNITT GLYPFEGDNI YKLFENIGKG SYAIPGDCGP PLSDLLKGML EYEPAKRFSI
RQIRQHSWFR KKHPPAEAPV PIPPSPDTKD RWRSMTVVPY LEDLHGADED EDLFDIEDDI
IYTQDFTVPG QVPEEEASHN GQRRGLPKAV CMNGTEAAQL STKSRAEGRA PNPARKACSA
SSKIRRLSAC KQQ
//

MIM 175200
*RECORD*
*FIELD* NO
175200
*FIELD* TI
#175200 PEUTZ-JEGHERS SYNDROME; PJS
;;POLYPOSIS, HAMARTOMATOUS INTESTINAL;;
POLYPS-AND-SPOTS SYNDROME
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder is due to mutations in the serine/threonine kinase STK11 gene
(602216).

DESCRIPTION

Peutz-Jeghers syndrome is an autosomal dominant disorder characterized
by melanocytic macules of the lips, buccal mucosa, and digits; multiple
gastrointestinal hamartomatous polyps; and an increased risk of various
neoplasms.

CLINICAL FEATURES

In the syndrome named for Peutz (1921) and Jeghers (Jeghers et al.,
1949), polyps may occur in any part of the gastrointestinal tract but
jejunal polyps are a consistent feature. Intussusception and bleeding
are the usual symptoms. Melanin spots of the lips, buccal mucosa, and
digits represent the second part of the syndrome. Malignant degeneration
of the small intestinal polyps is rare. Metastases from a malignant
polyp in Peutz-Jeghers syndrome was reported by Williams and Knudsen
(1965). Dodds et al. (1972) found 15 cases of gastrointestinal carcinoma
in Peutz-Jeghers syndrome: 5 in colon, 4 in duodenum, 4 in stomach, 1 in
ileum, and 1 in both jejunum and stomach. In the family reported by
Farmer et al. (1963), the father had only polyps, the son apparently
only pigmentation, and the daughter both polyps and pigmentation.
Kieselstein et al. (1969), who found polycystic kidney disease in the
same family, also noted a dissociation of signs. Brigg et al. (1976)
observed a case of presumed Peutz-Jeghers syndrome without spots or
positive family history. Hamartomatous polyps were limited to the
jejunum and caused bleeding. Griffith and Bisset (1980) reported 3
cases. In 2 of them, the family history was negative; in the third, the
father and a paternal uncle had melanin spots of the lips but no history
of intestinal disorder.

Sommerhaug and Mason (1970) added the ureter to the sites of polyps
described in the Peutz-Jeghers syndrome. Previously described
extraintestinal sites include esophagus, bladder, renal pelvis, bronchus
and nose. Burdick and Prior (1982) reported nonresectable adenocarcinoma
of the jejunum arising in a Peutz-Jeghers polyp and accompanied by
metastases in mesenteric lymph nodes. Two developed breast carcinoma of
which 1 arose in a fibroadenoma. Three had benign ovarian tumors, 1 had
a benign breast tumor and 1 had a benign colloid thyroid nodule. One of
the cases (case 7) reported by Jeghers et al. (1949) died of pancreatic
cancer. Bowlby (1986) reported pancreatic cancer in an adolescent boy
with PJS.

Affected females are prone to develop ovarian tumor, especially
granulosa cell tumor (Christian et al., 1964). Wilson et al. (1986)
described gynecomastia and multifocal and bilateral testicular tumors in
a 6-year-old boy with PJS. The testicular tumors appear to be of Sertoli
cell origin and most are calcifying. Two previously reported cases were
found. Coen et al. (1991) reported the case of a 4-year-old boy with
Peutz-Jeghers syndrome and bilateral sex-cord testicular tumors
resulting in gynecomastia. Studies led to the conclusion that increase
in aromatase activity (107910) in the gonadal tumors was responsible for
estrogen excess and gynecomastia. Three other reported male patients
with Peutz-Jeghers syndrome and gonadal tumors had presented with
gynecomastia between birth and 6 years of age. They pointed out that
multifocal sex-cord tumors were found in palpably normal testes. The
occurrence of ovarian tumors far exceeds that of testicular tumors in
this disorder. The production of estrogen by ovarian tumors is indicated
by the reported appearance of isosexual precocity in girls with PJS
(Solh et al., 1983). Young et al. (1995) reported 2 boys, aged 3.5 and
5.5 years, who were evaluated for gynecomastia and found to have
multicentric Sertoli cell testicular tumors responsible for their
feminization. Both had rapid growth and advanced bone age, and serum
levels of estradiol were markedly elevated.

Bergada et al. (2000) described a 7-year-old boy with Peutz-Jeghers
syndrome, gynecomastia, and bilateral neoplastic Sertoli cell
proliferation in whom the only abnormal hormonal profile was increased
concentration of inhibin-beta (see 147290), which was biologically
active, and pro-alpha C of insulin, which was biologically inactive.

In a patient with both psoriasis and Peutz-Jeghers syndrome (sine
polyps), Banse-Kupin and Douglass (1986) described a peculiar
phenomenon: the development of characteristic pigmented macules within
preexisting psoriatic plaques in sites highly unusual for PJS, e.g., on
the elbow, back of the neck and occipital scalp, buttocks, and legs.
Sommerhaug and Mason (1970) suggested that patients with PJS develop
polyps in areas of frequent trauma. Banse-Kupin and Douglass (1986)
proposed that pigmented macules may likewise be located in areas of
frequent trauma or areas of inflammation. Inflammation may induce
blockage of pigment transfer from melanocyte to keratinocyte, resulting
in a macule. As the inflammation or trauma subsides, so may the blockage
and the lesion may fade. Histologically, the oral mucosal lesions
resemble lentigo simplex, but the acral lesions are distinctive (Yamada
et al., 1981). There is an increased number of melanocytes with long
dendrites filled with melanosomes but few melanosomes in keratocytes,
suggesting a pigment block.

Giardiello et al. (1987) investigated the occurrence of cancer in 31
patients with PJS followed from 1973 to 1985. Gastrointestinal carcinoma
developed in 4, nongastrointestinal carcinoma in 10, and multiple
myeloma in 1. Adenomatous polyps of the stomach and colon occurred in 3
other patients. There were 4 cases of pancreatic cancer. Foley et al.
(1988) provided a 49-year follow-up of the 'Harrisburg family,' 3
affected members of which were reported by Jeghers et al. (1949). The
family had also been studied earlier by Bartholomew et al. (1962). In
all, 12 affected members have been identified, making this the largest
PJS kindred reported. One member of the family had developed a duodenal
carcinoma and a hamartoma with adenomatous changes. Another member
developed short bowel syndrome. In the follow-up of 72 patients with PJS
in the St. Mark's Polyposis Registry, Spigelman et al. (1989) found that
malignant tumors had developed in 16 (22%), of whom all but 1 had died.
There were 9 gastrointestinal and 7 nongastrointestinal tumors. The
chance of dying of cancer by age 57 was 48%.

Westerman and Wilson (1999) reviewed the literature on PJS, with
particular emphasis on the risks for PJS gene carriers. The risks
imposed by polyps included surgical emergencies like small bowel
intussusception, and chronic or acute bleeding from the polyps. Many
reports, however, suggested an association of PJS with both
gastrointestinal and nongastrointestinal malignancies, often at a young
age. The frequent occurrence of rare tumors of the ovary, cervix, and
testis indicated a general susceptibility for the development of
malignancies. The PJS gene was therefore thought to act as a tumor
suppressor gene. The authors suggested that a surveillance protocol
should be developed for the prevention of cancer in PJS.

Unusually early age of onset was observed by Fernandez Seara et al.
(1995) in a 15-day-old girl who was found to have generalized
gastrointestinal polyposis manifested by abdominal distention,
hematemesis, bloody diarrhea, and edema. At 15 days of age, ileocecal
intussusception causing intestinal obstruction was diagnosed
radiologically and reduced by hydrostatic enema; ileocecal surgical
resection was required, however. Rectal prolapse due to a large polyp
occurred at one month of age. Esophagogastroscopy showed polyps in the
stomach; one in the antrum partially obstructed the lumen. No
hyperpigmentation of the lips or oral mucosa was observed at any time
and none was present in her relatives. The histologic appearance of the
polyps removed during life and at autopsy was consistent with
Peutz-Jeghers syndrome.

Gruber et al. (1998) noted that the histopathologic appearance of
hamartomas in PJS is distinct from that of other types of
gastrointestinal polyps and likely reflects a different pathogenetic
sequence for their development. PJS hamartomas show an elongated,
frond-like epithelium with cystic dilatation of glands overlying an
arborizing network of smooth muscle bundles. Hypermucinous goblet cells
are often prominent. In addition, pseudoinvasion by histopathologically
benign epithelium is common in PJS hamartomas. These characteristic
features are easily distinguished from the cytologic atypia and lack of
differentiation seen in typical adenomas, and it is not surprising that
PJS tumors seem to share few of the earliest genetic events observed in
the transition of normal epithelium to dysplastic adenomas.
Hamartomatous polyps arising in the juvenile polyposis syndrome (174900)
originate through yet another mechanism as a consequence of germline
mutations in the SMAD4/DPC4 gene (600993). The hamartomas of juvenile
polyposis are histologically distinct from those of PJS, and the risk of
malignancy also differs in these 2 syndromes.

Some patients with PJS may be disturbed by the appearance of lentigines.
Kato et al. (1998) described ruby laser therapy of labial lentigines in
2 children with this disorder. They stated that the response to
treatment was excellent, with no sequelae or recurrence of the lesions.

Boardman et al. (2000) pointed out that diagnosing PJS, even in an
individual from a known PJS kindred, can be difficult. Oral pigmentation
tends to fade and be forgotten with time, and polyps can often be
asymptomatic. Additionally, other syndromes may mimic the pigmentation
of PJS, occurring in individuals with an occult malignancy (Babin et
al., 1978; Eng et al., 1991; Gass and Glatzer, 1991) or in individuals
with Laugier-Hunziker syndrome, a condition characterized by oral
hyperpigmentation without polyposis (Veraldi et al., 1991).

Familial hamartomatous polyps of the small intestine resembling those of
PJS were recognized as a feature of Bannayan-Zonana syndrome (BZS;
153480) by DiLiberti et al. (1983) and others. This disorder and Cowden
disease (158350) are caused by mutations in the PTEN1 gene. Pigmented
spots occur also in BZS but characteristically on the glans penis in
males and not on the lips.

In connection with the possibility that the melanin spots of the lips
represent a benign neoplasm, the observations of Jeghers et al. (1949)
may be significant: clinically, some of the spots could be seen to have
a somewhat stippled appearance under magnification, which, it was
thought, could be explained by a curious histologic pattern observed on
biopsy. The pigmentation occurred mainly in vertical bands interrupted
by unpigmented areas. The change suggested the possibility of clonality.

MAPPING

Studying 2 extended families, Bali et al. (1995) found positive evidence
for linkage with several microsatellite markers on chromosome 1. Seldin
(1997) reported that addition of more family members in the 2 largest
families decreased the lod scores substantially as did the addition of
more markers in the region. Indeed, in the original study, the maximum
2-point lod was below 2.0. Multipoint linkage analysis yielded a maximum
lod score of 4.00 at D1S220. This is located in the distal region of 1p,
where the human homolog of the putative modifier of multiple intestinal
neoplasias (172411) had previously been mapped.

In a patient with Peutz-Jeghers syndrome, Markie et al. (1996)
demonstrated a pericentric inversion in chromosome 6. Using fluorescence
in situ hybridization with YAC clones selected to contain genetic
markers from chromosome 6 and with a probe for the centromeric alphoid
array, they located 1 inversion breakpoint within the alphoid repeat
array, in a 1-cM interval between D6S257 and D6S402, and the other in a
4-cM interval between D6S403 and D6S311.

To localize the susceptibility locus for Peutz-Jeghers syndrome,
Hemminki et al. (1997) used comparative genomic hybridization (CGH) and
targeted linkage analysis, combined with loss of heterozygosity (LOH)
study. They demonstrated a high-penetrance locus in distal 19p with a
multipoint lod score of 7.00 at marker D19S886 without evidence of
genetic heterogeneity. The study demonstrated the power of CGH combined
with LOH analysis in identifying putative tumor suppressor loci. In
comparative genomic hybridization, a single hybridization allows DNA
copy number changes in the whole genome of a tumor to be assessed in
comparison with normal tissue DNA (Kallioniemi et al., 1992). The
findings of Hemminki et al. (1997) suggested that in most or all of the
families they studied, the PJS was caused by a defect in a single locus
on 19p. That the Peutz-Jeghers syndrome is genetically homogeneous
required, however, confirmation by linkage analysis in further families.
Amos et al. (1997) confirmed the mapping of PJS to the telomeric region
of 19p. In the 5 families examined, there were no recombinants with the
marker D19S886. The multipoint lod score at D19S886 was 7.52, and they
found no evidence for genetic heterogeneity or of reduced penetrance.

Mehenni et al. (1997) performed a genomewide linkage analysis, using DNA
polymorphisms in 6 families (2 from Spain, 2 from India, 1 from the
U.S., and 1 from Portugal), including 39 affected individuals and 6
individuals of unknown status. Marker D19S886 yielded a maximum lod
score of 4.74 at a recombination fraction of 0.45; multipoint linkage
analysis resulted in a lod score of 7.51 for the interval between
D19S886 and 19pter. However, markers on 19q13.4 also showed significant
evidence for linkage. For example, D19S880 resulted in a maximum lod
score of 3.8 at theta = 0.13. Most of this positive linkage was
contributed by a single family. Thus, the results confirmed the mapping
of a common PJS locus on 19p13.3, but also suggested the existence, in a
minority of families, of a potential PJS locus on 19q13.4. Buchet-Poyau
et al. (2002) excluded several candidate genes as a second PJS locus in
the 19q13.3-q13.4 region.

MOLECULAR GENETICS

Within a distance of 190 kb proximal to D19S886, the marker with the
highest lod score in the study of Hemminki et al. (1997), Jenne et al.
(1998) identified and characterized a novel human gene encoding the
serine/threonine kinase STK11. In a 3-generation PJS family, they found
an STK11 allele with a deletion of exons 4 and 5 and an inversion of
exons 6 and 7 (602216.0001) segregating with the disease. Sequence
analysis of STK11 exons in 4 unrelated PJS patients identified 3
nonsense mutations (602216.0002, 602216.0003, 602216.0004) and 1
acceptor splice site mutation (602216.0005). All 5 germline mutations
were predicted to disrupt the function of the kinase domain. Jenne et
al. (1998) concluded that germline mutations in STK11, probably in
conjunction with acquired genetic defects of the second allele in
somatic cells, caused the manifestations of PJS.

Independently and simultaneously, Hemminki et al. (1998), the group that
identified the linkage of PJS to chromosome 19, demonstrated mutations
in the serine/threonine kinase gene in 11 of 12 unrelated patients with
PJS.

Jenne (1998) speculated that cellular context between melanocytes and
keratinocytes are regulated by STK11 activity. He pointed to the wide
tissue distribution of STK11 and suggested that effects in melanocytes
may be observed preferentially at sites of mechanical and physical
stress.

Gruber et al. (1998) studied 6 families with PJS from the Johns Hopkins
Polyposis Registry to identify the molecular basis of PJS and to
characterize the pathogenesis of gastrointestinal hamartomas and
adenocarcinomas in these patients. Linkage analysis in the family
studied by McKusick, who contributed to the publication of Jeghers et
al. (1949), and in 5 other families confirmed linkage to 19p13.3.
Germline mutations in STK11 were identified in all 6 families by
sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from
patients with PJS identified LOH of 19p markers near STK11 in 70% of
tumors. Haplotype analysis indicated that the retained allele carried a
germline mutation (602216.0012), confirming that STK11 is a tumor
suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma
but not in hamartomas, implying that allelic loss of these 2 regions
corresponds to late molecular events in the pathogenesis of cancer in
PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53
by immunohistochemistry. None of the 18 PJS tumors showed microsatellite
instability, LOH on 5q near APC (611731), or mutations in codons 12 or
13 of the KRAS2 (190070) protooncogene. These data provided evidence
that STK11 is a tumor suppressor gene that acts as an early gatekeeper
regulating the development of hamartomas in PJS and suggested that
hamartomas may be pathogenetic precursors of adenocarcinoma. Additional
somatic mutation events underlie the progression of hamartomas to
adenocarcinomas, and some of these somatic mutations are common to the
later stages of tumor progression seen in the majority of colorectal
carcinomas.

Miyaki et al. (2000) presented findings suggesting that gastrointestinal
hamartomatous polyps in PJS patients develop through inactivation of the
STK11 gene by germline mutation plus somatic mutation or LOH of the
unaffected STK11 allele, and that additional mutations of the
beta-catenin gene (CTNNB1; 116806) and the p53 gene (TP53; 191170)
convert hamartomatous polyps into adenomatous and carcinomatous lesions.

Westerman et al. (1999) found novel STK11 mutations in 12 of 19
predominantly Dutch families with PJS. No mutation was found in the
remaining 7 families. None of the mutations occurred in more than 1
family, and a number were demonstrated to have arisen de novo. The
likelihood of locus heterogeneity was raised.

Jiang et al. (1999) conducted a detailed investigation of germline STK11
alterations by protein truncation test and genomic DNA sequence analysis
in 10 unrelated PJS families. A novel truncating deletion in a single
patient and several known polymorphisms were identified. The results
suggested that STK11 mutations account for only some cases of PJS.

Boardman et al. (2000) searched for mutations in the STK11 gene in 5
kindreds with more than 2 family members affected by PJS, 5 PJS probands
with only 1 other affected family member, and 23 individuals with
sporadic PJS. Conformation-sensitive gel electrophoresis was used for
the initial screen, followed by direct sequence analysis for
characterization. Long-range PCR was used for the detection of larger
genetic insertions or deletions. Genetic alterations in the gene were
found in 2 probands who had a family history of PJS. Mutations were
detected in the gene in only 4 of the 23 patients with sporadic PJS. The
authors interpreted these data as suggesting the presence of significant
genetic heterogeneity in PJS and the involvement of other loci in this
syndrome. They pointed to the report by Mehenni et al. (1997) of a
possible second susceptibility locus on 19q in 2 PJS Indian families and
to that by Olschwang et al. (1998), in which no evidence of linkage was
found in 3 of 20 PJS kindreds.

Olschwang et al. (2001) studied 34 families with PJS. Mutations in the
STK11 gene were identified in 24 families. In the 10 families in which
mutations were not identified, there was a significantly increased risk
of proximal biliary adenocarcinoma.

Westerman et al. (1999) traced the Dutch family reported by Peutz (1921)
and determined that the affected members carried a previously
unidentified germline mutation in the STK11 gene (602216.0014). The
pedigree, published by Westerman et al. (1999), showed affected
individuals in 4 generations and, by inference, in an earlier fifth
generation. In total, 22 persons (9 females and 13 males) were affected
and 31 were unaffected. Nasal polyposis was present in 2 members of 1
generation and in 4 members of another. Colicky abdominal pain occurred
in all 22 affected members, paralytic ileus in 16, chronic anemia in 9,
and acute or chronic blood loss in 14. Rectal prolapse due to polyps
occurred in 7. In 4 patients, the nasal polyposis was severe,
obstructing the nasal cavity and sinuses, requiring repeated surgery. In
1 woman who had had extremely severe nasal polyposis since childhood, a
squamous cell carcinoma of the nasal cavity developed. She died of this
tumor 4 years later. Three of the 5 cases of gastrointestinal cancer
were in the colon, 1 was in the stomach, and 1 was of unknown primary
origin. Breast cancer occurred in a female patient at the age of 47
years. Premenopausal breast cancer was diagnosed in a sib at the age of
44; it was not known whether this patient was affected by PJS. No other
cancers of the reproductive tract were found in this family.

Keller et al. (2002) reported molecular genetic evidence of an
association between nasal polyposis and PJS. They studied 12 nasal
polyps from 4 patients with PJS who came from 3 families with known
germline mutations in STK11, and 28 sporadic nasal polyps from 28
subjects without evidence of PJS, Kartagener syndrome (244400), cystic
fibrosis (CF; 219700), or aspirin sensitivity. In 2 unrelated patients
with PJS, 4 of 8 nasal polyps showed loss of heterozygosity at 19p13.3.
In contrast, loss of heterozygosity was not found in 23 sporadic nasal
polyps. Haplotype analysis showed that loss of heterozygosity comprised
deletion of the wildtype allele. Loss of heterozygosity at 19p13.3 in
nasal polyps of affected patients corresponded with reports of loss of
heterozygosity in gastrointestinal hamartomatous polyps (Entius et al.,
2001). In his original publication, Peutz (1921) suggested that nasal
polyps represent an extraintestinal manifestation of PJS.

Le Meur et al. (2004) reported a family with typical features of PJS,
including melanin spots of the oral mucosa, gastrointestinal
hamartomatous polyps, and breast and colon cancer. The authors noted
that the proband had neurofibromatosis type I (162200) of paternal
origin as well as PJS of maternal origin. Using quantitative multiplex
PCR of short fluorescent fragments of the 19p13 region, they identified
an approximately 250-kb heterozygous deletion that completely removed
the STK11 locus. Le Meur et al. (2004) stated that this was the first
report of a complete germline deletion of STK11 and suggested that the
presence of such large genomic deletions should be considered in PJS
families without detectable point mutations of STK11.

Amos et al. (2004) screened 42 independent probands for mutations in the
STK11 gene and detected mutations in 22 of 32 (69%) probands with PJS
and 0 of 10 probands referred to rule out PJS. In a total of 51
participants with PJS, the authors found gastric polyps to be very
common, with a median age at onset of 16 years. Individuals with
missense mutations had a significantly later time to onset of first
polypectomy (p = 0.04) and of other symptoms compared with those
participants with either truncating mutations or no detectable mutation.
Amos et al. (2004) concluded that STK11 mutation analysis should be
restricted to individuals who meet PJS criteria or their close
relatives, and suggested that mutation characterization might be of
value in disease management. They also noted that the common occurrence
of gastric polyps might facilitate chemopreventive studies for this
disorder.

In a 20-year-old female patient with PJS and gastrointestinal
hamartomatous polyps, Hernan et al. (2004) identified a de novo
heterozygous germline tyr246-to-ter mutation of the STK11 gene
(602216.0023). Comparison of melting curve profiles obtained from DNA
from the patient's lymphocytes and hamartomatous polyps showed no
differences, indicative of a heterozygous mutation rather than loss of
heterozygosity in the polyps. Hernan et al. (2004) suggested that
biallelic inactivation of STK11 is not necessarily required for
hamartoma formation in PJS patients.

In a patient with PJS and a primary gastric cancer (137215), Shinmura et
al. (2005) identified heterozygosity for a deletion mutation of the
STK11 gene (602216.0022), resulting in a truncated protein. No
inactivation of the wildtype allele by somatic mutation, chromosomal
deletion, or hypermethylation at the 5-prime CpG site of STK11 was
detected in the gastric carcinoma. The patient's sister also had PJS and
died of gastric carcinoma in her twenties. Shinmura et al. (2005) stated
that this was the first report of an STK11 germline mutation in a PJS
patient with gastric carcinoma.

- Genetic Heterogeneity

Alhopuro et al. (2008) identified a heterozygous germline mutation in
the MYH11 gene (160745) in 1 of 33 PJS patients who did not have STK11
mutations, and the mutation was not identified in 1,015 controls. The
patient had a cystic astrocytoma at age 13 years. At age 23 years, he
developed intussusception and was diagnosed with typical PJS. His
unaffected father also carried the mutation; there was no family history
of the disorder. The authors postulated autosomal recessive inheritance
and the presence of a second unidentified MYH11 mutation. In an
unrelated patient with colorectal tumor showing microsatellite
instability, Alhopuro et al. (2008) identified the same mutation in the
somatic state.

GENOTYPE/PHENOTYPE CORRELATIONS

In a study of 132 PJS patients with or without cancer who had mutations
in the STK11 gene, Schumacher et al. (2005) found that mutations in the
part of the gene involved in ATP binding and catalysis were rarely
associated with cancer, whereas mutations in the part of the gene
involved in substrate recognition were more frequently associated with
malignancies. PJS patients with breast cancers had predominantly
truncating mutations.

HISTORY

Although Peutz (1921) was the first to recognize the familial
association of gastrointestinal polyposis and mucocutaneous
pigmentation, cases of gastrointestinal and, in particular, polyposis of
the small intestine had been described before him. Many of these may
have been instances of Peutz-Jeghers syndrome in which the
characteristic pigmentation was not noticed or its significance was not
appreciated. Two extensive reviews put the polyps-and-spots syndrome 'on
the map': the review by Jeghers et al. (1949) in 2 successive weekly
issues of the New England Journal of Medicine, and, describing 10
personal cases, the review by Dormandy (1957) in 3 successive weekly
issues of the same journal. The designation Peutz-Jeghers syndrome
appears to have first been used (at least in the title of an article) by
Bruwer et al. (1954) of the Mayo Clinic. If in several early reports of
small intestinal polyposis the characteristic pigmentation of PJS may
have passed unnoticed, the reverse is certainly true. Jeghers et al.
(1949) called attention to the first account of such cases, in female
twins, by Hutchinson (1896). Hutchinson (1896) stated that the pigmented
spots 'remain nonaggressive and their subjects remain in good health.'
Weber (1919) reported that 'one of the twins had died at the age of 20
years of intussusception at the Metropolitan Hospital.' Jeghers et al.
(1949) obtained follow-up information on Hutchinson's twins of the
family name Howard. They were daughters of the official rat catcher of
city of London. The second twin died childless of breast cancer at the
age of 52 years. The breast cancer was considered coincidental at the
time of the follow-up, but the findings of Giardiello et al. (1987) and
the demonstration that the gene that is mutant in PJS is a tumor
suppressor gene, make the cause of death in the second twin highly
significant.

Keller et al. (2002) provided a history of the Peutz-Jeghers syndrome,
with biographic information concerning both Jan Peutz and Harold
Jeghers.

*FIELD* SA
Andre et al. (1966); Cantu et al. (1980); Cochet et al. (1979); Humphries
et al. (1966); Joishy et al. (1979); Keen and Murray (1962); Lehur
et al. (1984); Lin et al. (1977); Matuchansky et al. (1979); McAllister
et al. (1967); McAllister and Richards (1977); McKittrick et al. (1971);
Mehenni et al. (1998); Michalany and Ferraz (1962); Parker and Knight
(1983); Peloquin et al. (1981); Riley and Swift (1980); Scully (1970);
Sheward (1962); Tweedie and McCann (1984)
*FIELD* RF
1. Alhopuro, P.; Phichith, D.; Tuupanen, S.; Sammalkorpi, H.; Nybondas,
M.; Saharinen, J.; Robinson, J. P.; Yang, Z.; Chen, L.-Q.; Orntoft,
T.; Mecklin, J.-P.; Jarvinen, H.; and 12 others: Unregulated smooth-muscle
myosin in human intestinal neoplasia. Proc. Nat. Acad. Sci. 105:
5513-5518, 2008.

2. Amos, C. I.; Bali, D.; Thiel, T. J.; Anderson, J. P.; Gourley,
I.; Frazier, M. L.; Lynch, P. M.; Luchtefeld, M. A.; Young, A.; McGarrity,
T. J.; Seldin, M. F.: Fine mapping of a genetic locus for Peutz-Jeghers
syndrome on chromosome 19p. Cancer Res. 57: 3653-3656, 1997.

3. Amos, C. I.; Keitheri-Cheteri, M. B.; Sabripour, M.; Wei, C.; McGarrity,
T. J.; Seldin, M. F.; Nations, L.; Lynch, P. M.; Fidder, H. H.; Friedman,
E.; Frazier, M. L.: Genotype-phenotype correlations in Peutz-Jeghers
syndrome. J. Med. Genet. 41: 327-333, 2004.

4. Andre, R.; Duhamel, G.; Bruaire, M.; Tiollais, P.: Syndrome de
Peutz-Jeghers avec polypose oesophagienne. Bull. Mem. Soc. Med. Hop.
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syndrome maps to chromosome 1p. (Abstract) Am. J. Hum. Genet. 57
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7. Banse-Kupin, L. A.; Douglass, M. C.: Localization of Peutz-Jeghers
macules to psoriatic plaques. Arch. Derm. 122: 679-683, 1986.

8. Bartholomew, L. G.; Moore, C.; Dahlin, D. C.; Waugh, J. M.: Intestinal
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*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Nose];
Nasal polyps;
[Mouth];
Hyperpigmented macules of lips;
Hyperpigmented macules of buccal mucosa

RESPIRATORY:
[Airways];
Bronchial polyps

CHEST:
[Breasts];
Gynecomastia with Sertoli cell tumors

ABDOMEN:
[Biliary tract];
Biliary tract polyps;
[Gastrointestinal];
Hamartomatous polyps (stomach to rectum);
Recurrent colicky abdominal pain;
Intussusception;
Rectal prolapse;
Intestinal bleeding

GENITOURINARY:
[Internal genitalia, female];
Ovarian cysts;
[Ureters];
Ureteral polyps;
[Bladder];
Bladder polyps

SKELETAL:
[Hands];
Clubbing of fingers

SKIN, NAILS, HAIR:
[Skin];
Hyperpigmented spots on hands (especially palms), arms, feet (especially
plantar areas), legs, and lips

ENDOCRINE FEATURES:
Precocious puberty with Sertoli cell tumor

HEMATOLOGY:
Iron deficiency anemia

NEOPLASIA:
Gastrointestinal carcinoma;
Breast cancer (ductal);
Thyroid cancer;
Lung;
Pancreatic cancer;
Uterine cancer;
Sertoli cell testicular tumors;
Ovarian sex cord tumors

MISCELLANEOUS:
Pigmented spots appear in infancy through childhood and fade in adulthood;
Spots occur in 95% of patients but can be absent

MOLECULAR BASIS:
Caused by mutations in the serine/threonine protein kinase 11 gene
(STK11, 602216.0001)

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 08/15/2001

*FIELD* CN
Cassandra L. Kniffin - updated: 4/28/2008
Marla J. F. O'Neill - updated: 8/4/2005
Marla J. F. O'Neill - updated: 6/20/2005
Marla J. F. O'Neill - updated: 3/1/2005
Marla J. F. O'Neill - updated: 6/11/2004
Marla J. F. O'Neill - updated: 6/2/2004
Victor A. McKusick - updated: 1/15/2004
Victor A. McKusick - updated: 3/4/2003
Victor A. McKusick - updated: 2/24/2003
Victor A. McKusick - updated: 8/20/2002
Michael J. Wright - updated: 5/2/2002
Victor A. McKusick - updated: 2/26/2001
Victor A. McKusick - updated: 2/14/2001
Victor A. McKusick - updated: 8/17/2000
Wilson H. Y. Lo - updated: 12/2/1999
Wilson H. Y. Lo - updated: 10/27/1999
Victor A. McKusick - updated: 10/26/1999
Victor A. McKusick - updated: 5/12/1999
Victor A. McKusick - updated: 5/5/1999
Victor A. McKusick - updated: 2/16/1999
Victor A. McKusick - updated: 2/16/1998
Victor A. McKusick - updated: 1/21/1998
Victor A. McKusick - updated: 1/19/1998
Victor A. McKusick - updated: 12/29/1997
Victor A. McKusick - updated: 11/13/1997
Victor A. McKusick - updated: 2/10/1997

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

*FIELD* ED
terry: 10/12/2010
terry: 6/3/2009
wwang: 6/9/2008
ckniffin: 4/28/2008
ckniffin: 2/5/2008
alopez: 9/7/2007
terry: 12/22/2005
wwang: 8/5/2005
terry: 8/4/2005
wwang: 6/22/2005
wwang: 6/20/2005
terry: 4/21/2005
wwang: 3/3/2005
terry: 3/1/2005
carol: 2/8/2005
carol: 6/14/2004
terry: 6/11/2004
carol: 6/8/2004
terry: 6/2/2004
terry: 1/15/2004
terry: 11/13/2003
carol: 3/11/2003
terry: 3/4/2003
carol: 2/28/2003
tkritzer: 2/25/2003
terry: 2/24/2003
terry: 11/22/2002
tkritzer: 8/26/2002
tkritzer: 8/23/2002
terry: 8/20/2002
alopez: 5/2/2002
terry: 3/20/2001
joanna: 3/16/2001
cwells: 3/2/2001
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pfoster: 8/18/1994
warfield: 4/21/1994
carol: 7/9/1993

MIM 273300
*RECORD*
*FIELD* NO
273300
*FIELD* TI
#273300 TESTICULAR GERM CELL TUMOR; TGCT
;;MALE GERM CELL TUMOR; MGCT
SEMINOMA, INCLUDED;;
read moreNONSEMINOMATOUS GERM CELL TUMORS, INCLUDED;;
TERATOMA, TESTICULAR, INCLUDED;;
EMBRYONAL CELL CARCINOMA, INCLUDED;;
ENDODERMAL SINUS TUMOR, INCLUDED;;
SPERMATOCYTIC SEMINOMA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because testicular germ cell
tumors have been associated with somatic mutation in several genes; see
MOLECULAR GENETICS.

DESCRIPTION

Testicular germ cell tumors (TGCTs) affect 1 in 500 men and are the most
common cancer in males aged 15 to 40 in western European populations.
The incidence of TGCT rose dramatically during the 20th century. Known
risk factors for TGCT include a history of undescended testis (UDT),
testicular dysgenesis, infertility, previously diagnosed TGCT, and a
family history of the disease. Brothers of men with TGCT have an 8- to
10-fold risk of developing TGCT, whereas the relative risk to fathers
and sons is 4-fold. This familial relative risk is much higher than that
for most other types of cancer (summary by Rapley et al., 2000).

- Genetic Heterogeneity of Testicular Germ Cell Tumors

A locus for testicular germ cell tumors (TGCT1; 300228) has been
identified on chromosome Xq27.

CLINICAL FEATURES

Hutter et al. (1967) reviewed the reports of testicular tumors in
brothers and in twins and reported affected brothers.

Gustavson et al. (1975) reported bilateral testicular teratoma in 2
infant brothers with XXY Klinefelter syndrome. One of them also had
hydrocephalus due to stenosis of the aqueduct of Sylvius. Familial
occurrence of the Klinefelter syndrome is rare. The association of the
Klinefelter syndrome and testicular teratoma may be more than
coincidental because they have been observed together in other cases and
many testicular teratoma are both X-chromatin and Y-chromatin positive
suggesting that they are XXY.

Raghavan et al. (1980) reported a father who had sequential bilateral
seminomas and a son who had embryonal cell carcinoma and seminoma. The
authors reviewed 5 other reports of testicular tumors in father and son,
as well as 7 reports of concordant monozygotic twin pairs and 11 reports
of nontwin brothers. The report of Raghavan et al. (1980) illustrates
the dominant inheritance of hereditary tumors and their bilaterality
(e.g., acoustic neuroma, retinoblastoma, pheochromocytoma, etc.). The
sons (and other first-degree relatives) of men with bilateral tumors may
be at particular risk.

Shinohara et al. (1980) reported mature testicular teratoma in 2 first
cousins. Furthermore, the common grandparents were consanguineous, being
related as first cousins. The parent (i.e., the parent involved in the
consanguinity) of the teratoma-carrying boys was the mother in one case
and the father in the other. In a 10-member sibship in a
Spanish-American family, DiBella (1983) described testicular neoplasm in
3 brothers, benign ovarian neoplasms in 2 sisters, suspected benign
tumors of the uterus in 2 additional sisters, and a suspected testicular
mass in a fourth brother. Lynch et al. (1985) described the infantile
form of embryonal carcinoma of the testis in a 5-year-old boy and in a
23-year-old man who was the maternal half brother of his mother.
Copeland et al. (1986) reported testicular embryonal carcinoma in 2
brothers and a first cousin.

Von der Maase et al. (1986) found carcinoma in situ in the contralateral
testis in 27 of 500 patients (5.4%) with unilateral testicular germ cell
cancer. The estimated risk of developing invasive growth from the
contralateral testicular cancer was 40% within 3 years and 50% within 5
years. None of the 473 patients without carcinoma in situ detected by
screening biopsy developed contralateral testicular cancer after an
observation time ranging from 12 to 96 months. These observations
suggested to the authors that there is a subset of this type of
testicular cancer that is genetic and has a bilateral predisposition.
The authors suggested that all such carcinomas begin as carcinoma in
situ. Von der Maase et al. (1986) recommended that all patients with
unilateral testicular germ cell cancer should be offered biopsy of the
contralateral testis. Of the 27 patients, 16 had a cancer that was
labeled seminoma and 11 had a cancer that was considered to be
nonseminoma. It would be of great interest to know the median age of the
patients with contralateral carcinoma in situ as contrasted with the
others. If these represent a subset who had inherited 1 of the 2
mutations according to the Knudson theory, then the patients with
contralateral carcinoma in situ should have an earlier average age of
development of carcinoma.

Patel et al. (1990) reported 6 cases of familial testicular cancer: 4
father-son pairs, a pair of brothers, and a 23-year-old man who had a
maternal uncle with testicular cancer. In the U.K., according to Forman
et al. (1992), 42 families with 2 or more cases of testicular cancer
were reported to the familial testicular cancer registry. These families
included 2 pairs of identical twins, 27 sets of other brothers (25
pairs, 2 triples), 9 father-son pairs, 2 pairs of first cousins, and 2
uncle-nephew pairs. In all, 91 testicular tumors were described in 86
persons. Pure seminoma was present in 46% and other germ cell tumors in
54%. The median age at diagnosis was significantly younger than in a
comparable series of nonfamilial patients. The cumulative risk of
developing testicular cancer by the age of 50 years for a brother of a
patient was estimated to be 2.2%, which results in a relative risk of
9.8 in comparison with the general population. No significant
peculiarity of class I HLA type was found in a study of 21 affected sib
pairs.

Huddart et al.(1996) studied 3 families suggesting that there is a
familial predisposition to both male and female germ cell tumors. In 1,
the proband presented with a seminoma at the age of 51, his brother had
had a testicular teratoma at the age of 28, and their cousin had an
endodermal sinus tumor of the ovary diagnosed at 32 years. In the second
family, the index case presented with an undifferentiated malignant
teratoma at 28 years of age and his sister was diagnosed with bilateral
mature teratomatous cysts at the age of 39. In the third family, the
index case presented with a retroperitoneal teratoma at 26 years and his
sister was diagnosed with an ovarian dysgerminoma at 45 years. Huddart
et al. (1996) noted that none of these families had any features
indicative of the Li-Fraumeni syndrome (151623) or any other cancer
family syndrome. Trentini and Palmieri (1974) and Yule et al. (1994)
reported single families with ovarian and testicular germ cell tumors
and Jackson (1967) presented a family with multiple cases of
dysgerminoma.

Greene et al. (2010) noted that in familial cases the most common number
of affected family members was 2, that age at diagnosis was 2 to 3 years
younger for familial versus sporadic cases, and that familial TGCT were
more likely to be bilateral than sporadic TGCT.

- Association with Testicular Microlithiasis

Coffey et al. (2007) analyzed the frequency of testicular microlithiasis
(TM; 610441) in 169 patients with testicular germ cell tumor (TGCT), 58
relatives, and 101 controls and found that TM was more frequent in
unaffected male relatives of TGCT cases than controls and that patients
with a history of TGCT had a higher frequency of TM in their
contralateral remaining testis than controls. Coffey et al. (2007) also
demonstrated significant concordance of TM between relatives, raising
the hypothesis that TGCT and TM have a joint etiology.

Korde et al. (2008) performed testicular ultrasound in 48 men with
familial testicular cancer from 31 families with at least 2 cases of
TGCT, and in 33 of their unaffected male relatives. Testicular
microlithiasis (TM) was more frequent in the contralateral testicles of
men with a history of TGCT than in unaffected men (48% vs 24%; p =
0.04). The association appeared stronger for men with 5 or more
microliths than for those with less than 5 microliths. Testicular
microlithiases were bilateral in 6 (75%) of the 8 unaffected men in whom
they were detected. Among affected men, TM was not associated with
histology, age at diagnosis, or cancer treatment. Korde et al. (2008)
noted that TM was more prevalent among unaffected family members in this
study (24%) than previously described in the general population (0.6 to
9%), and that it appeared to cluster in certain families. The findings
suggested both a familial predisposition to TM and an association
between TM and TGCT.

POPULATION GENETICS

Forman et al. (1992) reported an epidemiologic study that showed an 8-
to 10-fold increase in relative risk of testicular cancer to brothers of
patients and a 4-fold increase in risk to fathers and sons. Families
with multiple cases of testicular cancer are rare and almost all those
reported have only 2 affected members.

Heimdal et al. (1996) found that 51 of 922 (5.5%) Norwegian patients
with testicular cancer and 5 of 237 (2.1%) Swedish patients had a
relative with confirmed testicular cancer. It was a first-degree
relative who was affected in the case of 32 of the probands.
Standardized incidence ratios (SIRs) were 10.2 for brothers, 4.3 for
fathers, and 5.7 for sons. The estimate for the risk to brothers in the
Norwegian part of the sample for development of testicular cancer by the
age of 60 was 4.1%. Patients with familial testicular cancer had
bilateral tumors more often than sporadic cases (9.8% bilaterality in
familial vs 2.8% in sporadic cases; P = 0.02). For patients with
seminoma, age of onset was lower in familial than in sporadic cases
(32.9 vs 37.6 years; P = 0.06). Heimdal et al. (1996) stated that the
prevalence of undescended testis did not seem to be higher in familial
than in sporadic testicular cancer.

Einhorn (2002) stated that the highest worldwide incidence of germ cell
tumors is in Scandinavian countries; by contrast, testicular cancer is
rare in African Americans. The primary age group is 15 to 35 years for
nonseminomatous tumors and a decade older for seminomas. Although cases
are few, germ cell tumors are important because they represent the most
common carcinoma in men aged 15 to 35 years and thus have the potential
to greatly shorten productive years of life. Available serum markers
such as alphafetoprotein (104150) and human chorionic gonadotropin have
allowed clinicians to make important and accurate treatment-related
decisions. Testicular cancer is a model for multidisciplinary care, as
surgical resection of postchemotherapy radiographically persistent
disease can improve the cure rate. Germ cell tumors have become an
excellent testing ground for experimental drugs, a number of which were
first approved by the Food and Drug Administration primarily on the
basis of data in testicular cancer.

INHERITANCE

Greene et al. (2010) reviewed the genetic risk factors and clinical
phenotype of familial testicular germ cell tumors in adults, noting that
although linkage analyses had identified several genomic regions of
modest interest, no high-penetrance cancer susceptibility gene had been
mapped to date, suggesting that the combined effects of multiple common
alleles, each conferring modest risk, might underlie familial testicular
cancer.

- L1 Methylation Status

Mirabello et al. (2010) studied global methylation at long interspersed
nuclear elements-1 (L1; 151626) in DNA from 152 patients with TGCT and
314 unaffected family members from 101 multiple-case testicular cancer
families. Analysis of the correlation of L1 methylation levels among
parent-child pairs independent of affection status revealed a strong
positive association only between mother-daughter (r = 0.48; p = 0.0002)
and father-daughter (r = 0.31; p = 0.021) pairs, suggesting
gender-specific inheritance of methylation. Incorporating cancer status
into the analysis revealed a strong correlation in L1 methylation levels
only among affected father-son pairs (r = 0.49; p = 0.03). There was a
marginally significant inverse association between lower L1 methylation
levels and increased risk of TGCT, compared to healthy male relatives (p
= 0.049). Mirabello et al. (2010) stated that their findings suggested
that heritability of L1 methylation might be gender-specific, and that
transgenerational inheritance of L1 methylation levels might be
associated with testicular cancer risk.

CYTOGENETICS

Studying direct preparations and 24-hr cultures, Atkin and Baker (1982)
found an isochromosome for the short arm of chromosome 12 in all of 10
seminomas, 1 malignant teratoma, and 1 combined seminoma and teratoma of
the testis. (The same workers found a possible isochromosome for 5p in
12 of 18 carcinomas of the cervix.) They also noted a relative excess of
normal chromosomes 12 in 4 of 5 of the seminomas analyzed in detail.
Castedo et al. (1989) found at least 1 copy of a 12p isochromosome in 8
of 10 seminomas. Thus, the authors concluded that amplification of 1 or
more genes on the short arm of chromosome 12 may be important in the
development of malignant testicular tumors. Chromosomal changes
presumably lead to the malignant phenotype by gene loss, gene
modification or gene amplification.

Samaniego et al. (1990) analyzed the karyotype of 24 male germ cell
tumors from both testicular and extragonadal sites and belonging to the
histologic categories seminoma, teratoma, embryonal carcinoma,
choriocarcinoma, and endodermal sinus tumor. In 90% of tumors, including
all histologic subtypes and both gonadal and extragonadal presentation,
they found isochromosome 12p. In contrast, they found del(12)(q13-q22)
exclusively in nonseminomatous GCTs, and mixed GCTs occurring in 44% of
such lesions. They developed a method based on DNA analysis for
detecting i(12p) as increased copy number of 12p. Furthermore, they
detected cytologic evidence of gene amplification in 12p in the form of
homogeneously staining regions (HSRs) and double minute chromosomes in
both treated and untreated primary extragonadal and metastatic GCTs.

Suijkerbuijk et al. (1991, 1992) applied competitive in situ
hybridization (CISH) techniques (Kievits et al., 1990) to show that the
aberrant chromosome in testicular germ cell tumors is indeed an
isochromosome 12p. Other marker chromosomes representing translocation
products that involve chromosome 12 were also identified. In the
studies, DNAs from 2 rodent-human somatic cell hybrids, containing
either a normal chromosome 12 or the p arm of chromosome 12 as their
unique human material, were used as probes. (Competitive in situ
hybridization, also referred to as chromosome painting, employs large
pools of cloned genomic sequences originating from a single human
chromosome as probe and involves a preannealing step in the presence of
an excess of sonicated total human DNA. It results in complete staining
of the particular chromosome in metaphase spreads and in interphase
nuclei. Kievits et al., 1990 stated that the approach permits detection
of hitherto undetectable chromosomal aberrations.)

In a cytogenetic analysis of 65 consecutively ascertained GCTs with
chromosomal abnormalities, Rodriguez et al. (1992) found that an
isochromosome for the short arm of chromosome 12 (i(12p)), monosomy 12,
and deletions in 12q occurred with frequencies of 86%, 11%, and 20%
respectively.

Because a marker chromosome interpreted as isochromosome 12p is present
in most testicular tumors of germ cell origin, Peltomaki et al. (1992)
investigated 22 patients with testicular germ cell tumors by Southern
blot hybridization to characterize changes in chromosome 12. In
comparison with normal DNA, tumor DNA of 18 patients showed increased
dosages of 12p accompanied by a comparable or smaller increase or no
change in the dosage of centromeric sequences of chromosome 12. The
interpretation offered by the authors was that most testicular tumors
had one or several isochromosomes for 12p that were formed by somatic
division of the centromere and that the points of breakage and reunion
in the centromeric region were different in different tumors.
Sex-limited parental imprinting was excluded by the fact that allelic
12p fragments showing increased intensity were paternal in 4 and
maternal in 3 of 7 informative cases. Furthermore, the observed patterns
of allelic fragments suggested that the marker isochromosome was formed
by sister chromatids of 1 homolog number 12 rather than the result of
interchange of genetic material between different homologs.

Ottesen et al. (2004) studied 3 brothers with germ cell tumors. One had
an intracranial tumor in the pineal region and the other 2 had
testicular tumors. No abnormalities were detected in peripheral blood
with karyotyping and molecular marker analysis of selected loci.
High-resolution comparative genomic hybridization (CGH) analysis of
microdissected histologic components of the overt tumors and the
adjacent carcinoma in situ demonstrated a pattern of genomic imbalances
characteristic for sporadic GCTs, including gain of 12p.

Stadler et al. (2012) investigated germline de novo copy number
variations (CNVs) in 382 genomes of 116 early-onset cancer case parent
trios and unaffected sibs. Unique de novo germline CNVs were not
observed in 107 breast or colon cancer trios or controls but were found
in 7% of 43 testicular germ cell tumor trios; this percentage exceeded
background CNV rates and suggested a rare de novo genetic paradigm for
susceptibility to some human malignancies.

MAPPING

- Genomewide Association Studies

Leahy et al. (1995) performed a sib-pair analysis on 35 families in
which there were either 2 or 3 affected brothers. These families were
typed for 220 autosomal microsatellite markers spaced 10-20 cM
throughout the genome. Six regions that gave a lod score of more than
1.0 on formal linkage analysis or a p value of 0.05 or less using a
nonparametric approach were considered as candidate regions for a
susceptibility gene. Of particular interest was one region on chromosome
4. A positive lod score of 2.6 on multipoint analysis was obtained with
2 neighboring probes in the region of 4cen-q13.

Rapley et al. (2009) performed a genomewide association study involving
730 TGCT cases and 1,435 controls, with replication in 571 cases and
1,806 controls, and found the strongest evidence for association with
dbSNP rs995030 (OR, 2.55; p = 1.0 x 10(-31)) and dbSNP rs1508595 (OR,
2.69; p = 2.6 x 10(-30)) that are both located within the same linkage
disequilibrium block on chromosome 12q22. Rapley et al. (2009) noted
that this region contains only 1 annotated protein-coding gene, KITLG
(184745), encoding the ligand for KIT, which has previously been
implicated in the pathogenesis of TGCT. There was also evidence for
susceptibility loci at dbSNP rs4624820 located 10-kb 3-prime of the
SPRY4 gene (607984) on chromosome 5q31.3 (per-allele odds ratio, 1.37; p
= 3.3 x 10(-13)) and at dbSNP rs210138 located in an intron of the BAK1
gene (600516) on chromosome 6p21.3-p21.2 (OR, 1.50; p = 1.1 x 10(-13)).

In a genomewide scan involving 277 TGCT cases and 919 controls, Kanetsky
et al. (2009) found 7 markers at chromosome 12q22 within the KITLG gene
that reached genomewide significance (p less than 5.0 x 10(-8)); in
independent replication using 371 TGCT cases and 860 controls, TGCT risk
increased 3-fold per copy of the major allele at dbSNP rs3782179 and
dbSNP rs4474514. The markers were associated with both seminoma and
nonseminoma TGCT subtypes.

Turnbull et al. (2010) conducted a genomewide association study for
testicular germ cell tumor, genotyping 298,782 SNPs in 979 affected
individuals and 4,947 controls from the U.K. and replicating
associations in a further 664 cases and 3,456 controls. Turnbull et al.
(2010) identified 3 novel susceptibility loci, 2 of which include genes
that are involved in telomere regulation. They identified 2 independent
signals within the TERT (187270)-CLPTM1L (612585) locus on chromosome
5p15.33, which had been associated with multiple other cancers (dbSNP
rs4635969, OR = 1.54, P = 1.14 x 10(-23); dbSNP rs2736100, OR = 1.33, P
= 7.55 x 10(-15)). Turnbull et al. (2010) also identified a locus on
chromosome 12 (dbSNP rs2900333, OR = 1.27, P = 6.16 x 10(-10)) that
contains ATF7IP, a regulator of TERT expression. Finally, Turnbull et
al. (2010) identified a locus on chromosome 9p24.3 (dbSNP rs755383, OR =
1.37, P = 1.12 x 10(-23)), containing the sex determination gene DMRT1
(602424), which has been linked to teratoma susceptibility in mice.

- Other Mapping Studies

Lothe et al. (1989) found loss of heterozygosity (LOH) for 3p or 11p
sequences in 40% of testicular cancers.

Mathew et al. (1994) analyzed chromosome 1 loss of heterozygosity in a
panel of 48 GCTs and observed allelic losses in 46% of cases on 1p and
in 23% of cases on 1q. There were 4 sites of frequent deletions, 3 in
the short arm (1p13, 1p22, and 1p32.2-p31.3) and 1 in the long arm
(1q32). Of the 11 probes on 1p that showed allelic losses, the highest
frequency of LOH was observed for D1S16 at 1p22 (38.5%). Teratomas
showed higher frequency of allelic losses (24.4%) compared to embryonal
carcinomas (9.5%), yolk sac tumors (12.1%), or seminomas (7.6%).

Rodriguez et al. (1992) presented data strongly suggested that loss of
genetic material on 12q characterizes the development of TGCTs. To
define the region of common deletion in GCTs at the molecular level,
Murty et al. (1992) compared germline and tumor genotypes for 8
polymorphic loci in paired normal/tumor DNA samples from 45 GCT
patients. Analysis demonstrated 2 regions of loss of constitutional
heterozygosity, one at 12q13 and the other at 12q22. One tumor exhibited
homozygous deletion of a region of 12q22 which includes the MGF gene
(184745). The MGF and KIT (164920) genes have been shown to play key
roles in embryonal and postnatal development of germ cells. The MGF gene
product constitutes the ligand for the receptor encoded by the KIT
protooncogene. They evaluated the expression of these 2 genes by
Northern blot analysis in a panel of 3 GCT cell lines and 24 fresh GCT
biopsies. Deregulated expression of MGF and KIT, which was discordant
between seminomatous and nonseminomatous lesions, was observed. Murty et
al. (1994) refined their data on the mapping of male germ cell tumors
(MGCTs). Using 5 dinucleotide repeats mapping to 12q22, they found LOH
in approximately 41% of tumors; one of the loci, D12S218, showed LOH in
37% of tumors, suggesting the presence of a tumor suppressor gene in its
vicinity. In this study, a panel of 66 tumor DNA samples and their
corresponding normal cells were investigated.

In a detailed deletion mapping analysis of 67 normal-tumor DNA
comparisons using 20 polymorphic markers mapped to 12q22-q24, Murty et
al. (1996) identified the limit of the minimal region of deletion at
12q22 between D12S377 (proximal) and D12S296 (distal). They constructed
a YAC contig map of a 3-cM region of this band and developed a radiation
hybrid (RH) map of the region. The consensus order developed by RH
mapping was in good agreement with the YAC STS-content map order. The RH
map estimated the distance between the D12S101 and D12S346 to be 246
cR(8000) and the minimal region of deletion to be 141 cR(8000).

Murty and Chaganti (1998) reviewed the genetics of male germ cell
tumors. A characteristic of GCTs is high sensitivity to cisplatin-based
chemotherapy. Chromosomal and molecular cytogenetic studies identified
multiplication of 12p, manifested in i(12p) or tandem duplication of
12p, as a unique change in GCTs which serves as a diagnostic marker.
Ectopic overexpression of cyclin D2 (CCND2; 123833), which maps to 12p,
as early as in carcinoma in situ, identified CCND2 as a candidate gene
in germ cell transformation. Genetic alterations identified in the tumor
suppressor genes DCC (120470), RB1 (614041), and nonmetastatic
protein-23 (NME1; 156490) in GCTs suggested that their inactivation
plays a key role in transformation or differentiation. The exquisite
sensitivity of these tumors to chemotherapy is reflected in their
overexpression of wildtype p53 protein and lack of TP53 mutations.

Zafarana et al. (2002) identified the DADR (609860), SOX5 (604975), and
ETNK1 (609858) genes within a region of chromosome 12p amplified in
testicular seminomas. Although all 3 genes were amplified to the same
level in seminomas with the amplification, only DADR expression was
significantly upregulated. DADR was also highly expressed in
nonseminomas of various histologies and derived cell lines lacking the
12p amplification. Low DADR expression was observed in normal testicular
parenchyma and in parenchyma containing carcinoma in situ. DADR
overexpression in seminomas and nonseminomas correlated with invasive
growth, reduced apoptosis, and earlier clinical manifestation.

In 97 patients with familial TGCT, 22 patients with sporadic bilateral
TGCT, and 871 controls, Kratz et al. (2011) genotyped 106 SNPs in 4
regions, in or near BAK1 on 6p21, DMRT1 on 9p24, KITLG on 12q, and
TERT-CLPTM1L on 5p15, all of which had previously been identified in
genomewide association studies of TGCT. Three previously identified risk
SNPs were replicated in the familial and sporadic bilateral TGCT
patients: dbSNP rs210138 within an intron of BAK1 (OR, 1.80; p = 7.03 x
10(-5)), dbSNP rs755383 near DMRT1 (OR, 1.67; p = 6.70 x 10 (-4)), and
dbSNP rs4635969 near TERT-CLPTM1L (OR, 1.59; p = 4.07 x 10(-3)).
Evidence for a second independent association was found for a SNP within
an intron of TERT, dbSNP rs4975605 (OR, 1.68; p = 1.24 x 10(-3)). In
addition, an association with another SNP in KITLG, dbSNP rs2046971, was
identified (OR 2.33; p = 1.28 x 10(-3)); this SNP is in high linkage
disequilibrium with the previously reported risk variant dbSNP rs995030.
Kratz et al. (2011) suggested that familial TGCT and sporadic bilateral
TGCT are polygenetic diseases caused by the same spectrum of genetic
risk factors.

- Y-Chromosome Microdeletion

A 1.6-Mb deletion of the Y chromosome that removes part of the AZFc
region--known as the gr/gr deletion (see 415000)--has been associated
with infertility. In epidemiologic studies, male infertility has shown
an association with testicular germ cell tumor (TGCT) that is out of
proportion with what can be explained by tumor effects. Thus, Nathanson
et al. (2005) hypothesized that the gr/gr deletion may be associated
with TGCT. They analyzed this deletion in a large series of TGCT cases
with or without a family history of TGCT. The gr/gr deletion was present
in 3% of TGCT cases with a family history. 2% of TGCT cases without a
family history, and 1.3% of unaffected males. The presence of the gr/gr
deletion was associated with a 2-fold increased risk of TGCT and a
3-fold increased risk of TGCT among patients with a positive family
history. The gr/gr deletion was more strongly associated with seminoma
TGCT than with nonseminoma TGCT. Thus, the Y microdeletion gr/gr appears
to be a rare, low penetrance allele that confers susceptibility to TGCT.

MOLECULAR GENETICS

- Variation in the BCL10 Gene and Progression to Advanced
Stage TGCT

Inoue et al. (2006) analyzed 4 SNPs in the BCL10 gene on chromosome
1p22, which had previously been identified in Japanese TGCTs by Kakinuma
et al. (2001), in 73 TGCT patients and 72 controls. No significant
difference in any of the 4 SNPs was observed between patients and
controls. However, GCT patients with metastatic disease were more likely
than patients with only local disease to carry a minor allele of either
of 2 SNPs in exon 1: 13G-T (A5S; adjusted odds ratio, 6.25, and p =
0.040) or 24C-G (L8L; adjusted odds ratio, 4.63 and p = 0.015). Inoue et
al. (2006) concluded that these BCL10 polymorphisms in exon 1 might play
a role in progression to advanced stage TGCTs.

- Somatic Mutation in the BLC10 Gene on Chromosome 1p22

Willis et al. (1999) analyzed 3 male germ cell tumor lines (Tera1,
Tera2, and GCT44) and identified 2, 3, and 1 mutations in the BCL10 gene
(603517), respectively (see, e.g., 603517.0001, 603517.0016, and
603517.0017).

Fakruddin et al. (1999) sequenced BCL10 in the 3 GCT cell lines
previously studied by Willis et al., 1999 but found no mutations.
Fakruddin et al. (1999) noted that their data were at variance with the
results reported by Willis et al. (1999), and concluded that BCL10 is
not a target tumor suppressor gene at 1p22 in GCTs.

Van Schothorst et al. (1999) screened exons 2 and 3 of the BCL10 gene in
a series of TGCT-derived and related cell lines, including the 3 GCT
cell lines previously studied by Willis et al., 1999, as well as primary
tumors. No aberrations were detected by SSCP on genomic DNA or
restriction endonuclease digestion analysis of PCR-amplified fragments,
and van Schothorst et al. (1999) concluded that inactivation of BCL10 by
genomic events in TGCTs is not involved in the majority of cases, if at
all.

Lee et al. (1999) analyzed the BCL10 gene by PCR-SSCP using DNA
extracted from malignant and normal cells of 439 paraffin-embedded tumor
tissue samples, including 78 GCTs. Enrichment and direct sequencing of
aberrantly migrating bands led to the identification of somatic
mutations in 2 (2.6%) of the 78 TGCTs (both were mature teratomas; see,
e.g., 603517.0018). Lee et al. (1999) concluded that BCL10 may
occasionally be involved in the pathogenesis of TGCTs, but that the
absence or low frequency of mutation suggested that either BCL10 is
inactivated by other mechanisms or that it is not the only target of
chromosome 1p22 deletion in human tumors.

Kakinuma et al. (2001) found loss of heterozygosity at chromosome 1p in
21 (42%) of 49 Japanese TGCTs, including 12 (43%) of 28 seminomas and 8
(38%) of 21 nonseminomatous GCTs. No somatic mutations were identified
by SSCP and direct sequencing in any of the tumors, although 4 SNPs were
detected.

- Somatic Mutation in the FGFR3 Gene on Chromosome 4p16

Goriely et al. (2009) screened 30 spermatocytic seminomas for oncogenic
mutations in 17 genes and identified a K650E mutation in FGFR3
(134934.0004) in 2 tumors.

- Somatic Mutation in the KIT Gene on Chromosome 4q12

Tian et al. (1999) identified an asp816-to-his mutation in the KIT gene
(164920.0021) in primary tissue samples from patients with germ cell
tumors.

- Somatic Mutation in the BRAF Gene on Chromosome 7q34

Sommerer et al. (2005) analyzed the BRAF gene (164757) in 30 seminomas
and 32 nonseminomatous GCTs with a mixture of embryonal carcinoma, yolk
sac tumor, choriocarcinoma, and mature teratoma. The activating BRAF
missense mutation 1796T-A (164757.0001) was identified in 3 (9%) of 32
nonseminomatous tumors, within the embryonic carcinoma component; no
BRAF mutations were found in the seminomas. There was no correlation
between BRAF mutation status and tumor stage or grade or other
histopathologic factors.

- Somatic Mutation in the HRAS Gene on Chromosome 11p15.5

Goriely et al. (2009) screened 30 spermatocytic seminomas for oncogenic
mutations in 17 candidate genes and identified apparent homozygosity for
5 mutations in the HRAS gene (190020), 3 182A-G transitions and 2 181C-A
transversions, all involving the Q61 codon (see, e.g., 190020.0002).

- Somatic Mutation in the KRAS Gene on Chromosome 12p12

Sommerer et al. (2005) analyzed the KRAS gene (190070) in 30 seminomas
and 32 nonseminomatous GCTs 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. The KRAS mutations in the nonseminomas occurred
within the embryonal carcinoma component in 2 and within the
choriocarcinoma in 1. No correlation between KRAS mutation pattern and
histopathologic variables was observed.

- Somatic Mutation in the STK11 Gene on Chromosome 19p13

Avizienyte et al. (1998) identified a somatic gly163-to-asp mutation in
the STK11 gene (602216.0011) in a case of sporadic testicular carcinoma.

- Exclusion Studies

Murty et al. (1996) excluded 4 genes on chromosome 12q22 as candidates
for familial testicular cancer: mast cell growth factor (184745), B-cell
translocation gene-1 (109580), thymopoietin (188380), and neural
precursor cell expressed, developmentally down-regulated-1 (600372).

ANIMAL MODEL

In laboratory mice, testicular germ cell tumors (TGCTs) arise from
primordial germ cells (PGC) in only the inbred 129 strain, and
susceptibility is under multigenic control (Stevens and Hummel, 1957).
The spontaneously arising mutation Ter (Stevens, 1973) on mouse
chromosome 18 (Asada et al., 1994; Sakurai et al., 1994) increases TGCT
frequency on a 129/Sv background.

Inbred 129 strain mice are predisposed to developing male germ cell
tumors (GCTs) of the testes. GTC incidence is increased in 129 strain
males that lack functional p53 protein (191170). Muller et al. (2000)
used this finding to facilitate the generation of panels of GCT-bearing
intercross and backcross mice for genetic mapping analysis. A 129 strain
locus, designated pgct1, that segregated with the male GCT phenotype was
identified on mouse chromosome 13 near D13Mit188. This region of mouse
chromosome 13 may have conservation of synteny with a portion of human
chromosome 5q that is implicated in male GCT susceptibility in humans.

Youngren et al. (2005) reported the positional cloning of Ter, revealing
a point mutation that introduces a termination codon in the mouse Dnd1
gene (609385). PGC deficiency was corrected both with BACs containing
Dnd1 and with a Dnd1-encoding transgene. Dnd1 is expressed in fetal
gonads during the critical period when TGCTs originate. Dnd1 has an RNA
recognition motif and is most similar to the apobec (see 600130)
complementation factor, a component of the cytidine to uridine RNA
editing complex. These results suggested that Ter may adversely affect
essential aspects of RNA biology during PGC development. Youngren et al.
(2005) stated that Dnd1 was the first protein known to have an RNA
recognition motif directly implicated as a heritable cause of
spontaneous tumorigenesis, and they suggested that TGCT development in
the 129-Ter mouse strain models pediatric TGCTs in humans.

Collin et al. (1996), in a genome scan of tumor-bearing progeny from
backcrosses between the 129/Sv-Ter/+ and MOLF/Ei strains provided modest
evidence that MOLF-derived alleles on mouse chromosome 19 enhance
development of bilateral TGCTs. To obtain independent evidence for
linkage to the MOLF chromosome, Matin et al. (1999) made an autosomal
chromosome substitution strain (a so-called consomic strain, or CSS), in
which chromosome 19 of 129/Sv +/+ was replaced by its MOLF-derived
homolog. The unusually high frequency of TGCTs in this CSS (even in the
absence of the Ter mutation) provided evidence confirming the genome
survey results, identified linkage for a naturally occurring strain
variant allele that confers susceptibility to TGCTs, and illustrated the
power of CSSs in complex trait analysis.

The agouti (ASIP; 600201)-yellow (Ay) deletion is the only genetic
modifier known to suppress testicular germ cell tumor (TGCT)
susceptibility in mice or human. The Ay mutation deletes Raly and Eif2s2
(603908) and induces the ectopic expression of agouti, all of which are
potential TGCT-modifying mutations. Heaney et al. (2009) reported that
the reduced TGCT incidence of heterozygous Ay male mice and the
recessive embryonic lethality of Ay are caused by the deletion of
Eif2s2, the beta subunit of translation initiation factor eIF2. The
incidence of affected males was reduced 2-fold in mice that were
partially deficient for Eif2s2 and that embryonic lethality occurred
near the time of implantation in mice that were fully deficient for
Eif2s2. In contrast, neither reduced expression of Raly in gene-trap
mice nor ectopic expression of agouti in transgenic or viable-yellow
(Avy) mutants affected TGCT incidence or embryonic viability. Partial
deficiency of Eif2s2 attenuated germ cell proliferation and
differentiation, both of which are important to TGCT formation. Heaney
et al. (2009) concluded that germ cell development and TGCT pathogenesis
are sensitive to the availability of the eIF2 translation initiation
complex and to changes in the rate of translation.

*FIELD* SA
Zevallos et al. (1983)
*FIELD* RF
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*FIELD* CS
INHERITANCE:
Isolated cases

GENITOURINARY:
[Internal genitalia, male];
Painless testicular mass

NEOPLASIA:
Male germ cell tumors (GCT), 2 subtypes -;
Seminoma;
Nonseminoma (embryonal carcinoma, teratoma, choriocarcinoma, endodermal
sinus tumor)

LABORATORY ABNORMALITIES:
Isochromosome 12p (i(12p));
Elevated hCG (choriocarcinoma);
Elevated AFP (endodermal sinus tumor);
Elevated hCG or AFP or both (embryonal carcinoma);
Azoospermia/oligospermia (present at diagnosis)

MISCELLANEOUS:
Two subtypes - seminoma and nonseminoma;
Occasionally germ cell tumor arise from extra gonadal site (e.g.,
mediastinum, retroperitoneum, pineal gland);
Most common cancer in men aged 15-40 years;
Highest incidence in men of European descent;
Risk factors for development of TGCT - family history, cryptorchidism
(219050), testicular feminization (300068), Klinefelter syndrome,
previous TGCT, gonadal dysgenesis

*FIELD* CN
Kelly A. Przylepa - revised: 5/12/2006

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 09/10/2012
joanna: 2/1/2007
joanna: 5/12/2006
alopez: 12/19/2005

*FIELD* CN
Ada Hamosh - updated: 10/15/2013
Marla J. F. O'Neill - updated: 11/29/2011
Marla J. F. O'Neill - updated: 11/23/2011
Marla J. F. O'Neill - updated: 8/3/2011
Ada Hamosh - updated: 11/10/2010
George E. Tiller - updated: 11/25/2009
Marla J. F. O'Neill - updated: 9/10/2009
Marla J. F. O'Neill - updated: 8/10/2009
Patricia A. Hartz - updated: 1/30/2006
Victor A. McKusick - updated: 12/12/2005
Ada Hamosh - updated: 6/3/2005
Victor A. McKusick - updated: 2/25/2004
Victor A. McKusick - updated: 10/11/2002
Victor A. McKusick - updated: 9/29/1999
Victor A. McKusick - updated: 8/21/1998

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 10/15/2013
carol: 11/30/2011
carol: 11/29/2011
carol: 11/23/2011
wwang: 8/8/2011
terry: 8/3/2011
carol: 6/17/2011
alopez: 11/12/2010
terry: 11/10/2010
alopez: 3/2/2010
wwang: 1/6/2010
terry: 11/25/2009
wwang: 9/22/2009
terry: 9/10/2009
wwang: 8/18/2009
terry: 8/10/2009
terry: 6/3/2009
terry: 3/25/2009
carol: 5/3/2007
mgross: 1/30/2006
alopez: 12/19/2005
terry: 12/12/2005
wwang: 6/7/2005
wwang: 6/3/2005
terry: 6/2/2004
carol: 3/17/2004
tkritzer: 2/26/2004
terry: 2/25/2004
tkritzer: 9/17/2003
tkritzer: 10/18/2002
tkritzer: 10/11/2002
terry: 11/24/1999
alopez: 11/4/1999
alopez: 9/30/1999
terry: 9/29/1999
carol: 8/24/1998
terry: 8/21/1998
carol: 6/16/1998
terry: 11/6/1997
mark: 9/10/1996
terry: 8/23/1996
mark: 5/9/1996
terry: 5/2/1996
terry: 3/29/1996
mark: 2/17/1996
mark: 2/12/1996
mark: 9/22/1995
carol: 12/1/1994
terry: 7/27/1994
mimadm: 7/7/1994
jason: 6/27/1994
warfield: 3/10/1994

MIM 602216
*RECORD*
*FIELD* NO
602216
*FIELD* TI
*602216 SERINE/THREONINE PROTEIN KINASE 11; STK11
;;LKB1
*FIELD* TX

CLONING

Jenne et al. (1998) identified and characterized a novel human gene
read moreencoding the serine/threonine kinase STK11 within a region on chromosome
19p13.3 identified as a locus for Peutz-Jeghers syndrome (PJS; 175200)
by Hemminki et al. (1997). A sequence similarity search in GenBank with
the genomic sequence obtained from the telomeric end of a cosmid from
the PJS region revealed identity of 32 bp with a coding region of a
human serine/threonine protein kinase, previously named LKB1 but renamed
STK11. To prove that STK11 was indeed located in this region, Jenne et
al. (1998) selected primers from the 5-prime and 3-prime ends of the
STK11 cDNA sequence for direct sequence analysis of the cosmid.

GENE FUNCTION

Smith et al. (1999) found that the mouse Lkb1 gene encodes a protein
showing strong sequence similarity to human LKB1. The 3-prime end of
Lkb1 in the mouse was found to lie in very close proximity to the
3-prime end of an apparently unrelated gene called R29144/1, and it
seemed probable that overlapping transcripts of the 2 genes are
produced. Using transfection of Lkb1 cDNAs, Smith et al. (1999) showed
that Lkb1 is most likely a nuclear protein; furthermore, they defined a
nuclear localization signal within the protein sequence. Smith et al.
(1999) hypothesized that the defect in PJS may result directly in
changes in gene expression in the nucleus of target cells.

Karuman et al. (2001) demonstrated that LKB1 physically associates with
p53 (191170) and regulates specific p53-dependent apoptosis pathways.
LKB1 protein is present in both the cytoplasm and nucleus of living
cells and translocates to mitochondria during apoptosis. In vivo, LKB1
is highly upregulated in pyknotic intestinal epithelial cells. In
contrast, polyps arising in PJS patients are devoid of LKB1 staining and
have reduced numbers of apoptotic cells. The authors proposed that a
deficiency in apoptosis is a key factor in the formation of multiple
benign intestinal polyps in PJS patients, and possibly for the
subsequent development of malignant tumors in these patients.

Smith et al. (2001) used a yeast 2-hybrid system to identify a novel
leucine-rich repeat containing protein, which they called LIP1 (607172),
that interacts with LKB1. The LIP1 gene encodes a cytoplasmic protein of
121 kD. When LKB1 and LIP1 were coexpressed in vitro, the proportion of
cytoplasmic LKB1 dramatically increased, suggesting that LIP1 may
regulate LKB1 function by controlling its subcellular localization.
Ectopic expression of both LKB1 and LIP1 in Xenopus embryos induced a
secondary body axis, resembling the effects of ectopic expression of
TGF-beta (190180) superfamily members and their downstream effectors.
Furthermore, LIP1 interacted with the TGF-beta-regulated transcription
factor SMAD4 (600993), forming a LKB1-LIP1-SMAD4 ternary complex. Since
SMAD4 mutations give rise to juvenile intestinal polyposis syndrome
(PJI; 174900), the authors suggested that a mechanistic link may exist
between PJI and PJS.

Restoring LKB1 activity into cancer cell lines defective for its
expression results in a G1 cell cycle arrest. Tiainen et al. (2002)
showed that reintroduced active LKB1 was cytoplasmic and nuclear,
whereas most kinase-defective PJS mutants of LKB1 localized
predominantly to the nucleus. Moreover, when LKB1 was forced to remain
cytoplasmic through disruption of the nuclear localization signal, it
retained full growth suppression activity in a kinase-dependent manner.
LKB1-mediated G1 arrest was found to be bypassed by coexpression of the
G1 cyclins cyclin D1 (168461) and cyclin E (123827). Protein levels of
the CDK inhibitor p21 (116899) and p21 promoter activity were
specifically upregulated in LKB1-transfected cells. Both the growth
arrest and the induction of the p21 promoter were found to be p53
(191170)-dependent. The authors suggested that growth suppression by
LKB1 is mediated through signaling of cytoplasmic LKB1 to induce p21
through a p53-dependent mechanism.

Martin and St Johnston (2003) demonstrated that Drosophila Lkb1 is
required for the early anterior-posterior polarity of the oocyte, and
for the repolarization of the oocyte cytoskeleton that defines the
embryonic anterior-posterior axis. Lkb1 is phosphorylated by Par1 in
vitro, and overexpression of Lkb1 partially rescues the Par1 phenotype.
These 2 kinases, therefore, function in a conserved pathway for axis
formation in flies and worms. Lkb1 mutant clones also disrupt
apical-basal epithelial polarity, suggesting a general role in cell
polarization. Martin and St Johnston (2003) showed that Drosophila Lkb1
is phosphorylated by protein kinase A (PKA; see 176911) at a conserved
site that is important for its activity. Thus, Martin and St Johnston
(2003) suggested that Drosophila and human LKB1 may be functional
homologs, and that it may be the loss of cell polarity that contributes
to tumor formation in individuals with PJS.

Baas et al. (2003) showed that endogenous LKB1 and STRAD (608626) form a
complex in which STRAD activates LKB1, resulting in phosphorylation of
both partners. STRAD determined the subcellular localization of
wildtype, but not mutant, LKB1, translocating it from nucleus to
cytoplasm. An LKB1 mutation identified in a family with Peutz-Jeghers
syndrome (175200) that did not compromise LKB1 kinase activity
interfered with LKB1 binding to STRAD, and hence with STRAD-dependent
regulation. Removal of endogenous STRAD by small interfering RNA
abrogated LKB1-induced G1 arrest.

Baas et al. (2004) constructed intestinal epithelial cell lines in which
inducible STRAD activated LKB1. Upon LKB1 activation, single cells
rapidly remodeled their actin cytoskeletons to form apical brush
borders. The junctional proteins ZO1 (601009) and p120 (CTNND1; 601045)
redistributed in a dotted circle peripheral to the brush border, in the
absence of cell-cell contacts. Apical and basolateral markers sorted to
their respective membrane domains. Baas et al. (2004) concluded that
LKB1 can induce complete polarity in intestinal epithelial cells, which
can fully polarize in the absence of junctional cell-cell contacts.

Mehenni et al. (2005) identified PTEN (601728) as an LKB1-interacting
protein. Several LKB1 point mutations associated with PJS disrupted the
interaction with PTEN, suggesting that loss of this interaction might
contribute to PJS. Although PTEN and LKB1 are predominantly cytoplasmic
and nuclear, respectively, their interaction led to a cytoplasmic
relocalization of LKB1. PTEN was found to be a substrate of the kinase
LKB1 in vitro. As PTEN is a dual phosphatase mutated in autosomal
inherited disorders with phenotypes similar to those of PJS, such as
Bannayan-Riley-Ruvalcaba syndrome (153480) and Cowden disease (158350),
Mehenni et al. (2005) suggested a functional link between the proteins
involved in different hamartomatous polyposis syndromes and emphasized
the central role played by LKB1 as a tumor suppressor in the small
intestine.

Ji et al. (2007) used a somatically activatable mutant Kras-driven model
of mouse lung cancer to compare the role of Lkb1 to other tumor
suppressors in lung cancer. Although Kras mutation cooperated with loss
of p53 (191170) or Ink4a/Arf (also known as Cdkn2a, 600160), in this
system, the strongest cooperation was seen with homozygous inactivation
of Lkb1. Lkb1-deficient tumors demonstrated shorter latency, an expanded
histologic spectrum (adeno-, squamous, and large-cell carcinoma), and
more frequent metastasis compared to tumors lacking p53 or Ink4a/Arf.
Pulmonary tumorigenesis was also accelerated by hemizygous inactivation
of Lkb1. Consistent with these findings, inactivation of LKB1 was found
in 34% and 19% of 144 analyzed human lung adenocarcinomas and squamous
cell carcinomas, respectively. Expression profiling in human lung cancer
cell lines and mouse lung tumors identified a variety of
metastasis-promoting genes, such as NEDD9 (602265), VEGFC (601528), and
CD24 (600074), as targets of LKB1 repression in lung cancer. Ji et al.
(2007) concluded that their studies establish LKB1 as a critical barrier
to pulmonary tumorigenesis, controlling initiation, differentiation, and
metastasis.

Katajisto et al. (2008) demonstrated that either monoallelic or
biallelic loss of murine STK11 limited to transgelin (TAGLN;
600818)-expressing mesenchymal cells resulted in premature postnatal
death as a result of gastrointestinal polyps indistinguishable from
those in Peutz-Jeghers syndrome. STK11-deficient mesenchymal cells
produced less TGF-beta (190180), and defective TGF-beta signaling to
epithelial cells coincided with epithelial proliferation. Katajisto et
al. (2008) also noted TGF-beta signaling defects in polyps of
individuals with Peutz-Jeghers syndrome, suggesting that the identified
stromal-derived mechanism of tumor suppression is also relevant in
Peutz-Jeghers syndrome.

Nakada et al. (2010) found that deletion of the Lkb1 gene in mice caused
increased hematopoietic stem cell (HSC) division, rapid HSC depletion,
and pancytopenia. HSCs depended more acutely on Lkb1 for cell cycle
regulation and survival than many other hematopoietic cells. HSC
depletion did not depend on mammalian target of rapamycin (mTOR; 601231)
activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid
progenitors, had reduced mitochondrial membrane potential and ATP
levels. HSCs deficient for 2 catalytic alpha-subunits of AMP-activated
protein kinase (AMPK; e.g., 602739) showed similar changes in
mitochondrial function but remained able to reconstitute irradiated
mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited
defects in centrosomes and mitotic spindles in culture, and became
aneuploid. Nakada et al. (2010) concluded that Lkb1 is therefore
required for HSC maintenance through AMPK-dependent and AMPK-independent
mechanisms, revealing differences in metabolic and cell cycle regulation
between HSCs and some other hematopoietic progenitors.

Gurumurthy et al. (2010) independently showed that the Lkb1 tumor
suppressor is critical for the maintenance of energy homeostasis in
hematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC
quiescence followed by rapid depletion of all hematopoietic
subpopulations. Lkb1-deficient bone marrow cells exhibited mitochondrial
defects, alterations in lipid and nucleotide metabolism, and depletion
of cellular ATP. The hematopoietic effects are largely independent of
Lkb1 regulation of AMPK and mTOR signaling. Gurumurthy et al. (2010)
concluded that their data defined a central role for Lkb1 in restricting
HSC entry into cell cycle and in broadly maintaining energy homeostasis
in hematopoietic cells through a novel metabolic checkpoint.

Gan et al. (2010) showed that Lkb1 has an essential role in HSC
homeostasis. They demonstrated that ablation of Lkb1 in adult mice
results in severe pancytopenia and subsequent lethality. Loss of Lkb1
leads to impaired survival and escape from quiescence of HSCs, resulting
in exhaustion of the HSC pool and a marked reduction of HSC repopulating
potential in vivo. Lkb1 deletion has an impact on cell proliferation in
HSCs, but not on more committed compartments, pointing to
context-specific functions for Lkb1 in hematopoiesis. The adverse impact
of Lkb1 deletion on hematopoiesis was predominantly cell-autonomous and
mTOR complex 1-independent, and involves multiple mechanisms converging
on mitochondrial apoptosis and possibly downregulation of PGC1
coactivators (see 604517) and their transcriptional network, which have
critical roles in mitochondrial biogenesis and function. Thus, Gan et
al. (2010) concluded that Lkb1 serves as an essential regulator of HSCs
and hematopoiesis, and more generally, points to the critical importance
of coupling energy metabolism and stem cell homeostasis.

Using overexpression and knockdown studies with cultured rat and mouse
hippocampal and cortical neurons, Matsuki et al. (2010) found that a
signaling pathway containing Stk25 (602255), Lkb1, Strad, and the Golgi
protein Gm130 (GOLGA2; 602580) promoted Golgi condensation and multiple
axon outgrowth while inhibiting Golgi deployment into dendrites and
dendritic growth. This signaling pathway acted in opposition to the
reelin (RELN; 600514)-Dab1 (603448) pathway, which tended to inhibit
Golgi condensation and axon outgrowth and favor Golgi deployment into
dendrites and dendrite outgrowth.

AMPK is an alpha-beta-gamma heterotrimer activated by decreasing
concentrations of adenosine triphosphate (ATP) and increasing AMP
concentrations (summary by Oakhill et al., 2011). AMPK activation
depends on phosphorylation of the alpha catalytic subunit on thr172 by
kinases LKB1 or CaMKK-beta (CAMKK2; 615002), and this is promoted by AMP
binding to the gamma subunit (602742). AMP sustains activity by
inhibiting dephosphorylation of alpha-thr172, whereas ATP promotes
dephosphorylation. Oakhill et al. (2011) found that adenosine
diphosphate (ADP), like AMP, bound to gamma sites 1 and 3 and stimulated
alpha-thr172 phosphorylation. However, in contrast to AMP, ADP did not
directly activate phosphorylated AMPK. In this way, both ADP/ATP and
AMP/ATP ratios contribute to AMPK regulation.

Denning et al. (2012) identified a mechanism of cell extrusion that is
caspase-independent and that can eliminate a subset of the C. elegans
cells programmed to die during embryonic development. In wildtype
animals, these cells die soon after their generation through
caspase-mediated apoptosis. However, in mutants lacking all 4 C. elegans
caspase genes, these cells were eliminated by being extruded from the
developing embryo into the extraembryonic space of the egg. The shed
cells showed apoptosis-like cytologic and morphologic characteristics,
indicating that apoptosis can occur in the absence of caspases in C.
elegans. Denning et al. (2012) described a kinase pathway required for
cell extrusion involving Par4, Strd1, and Mop25.1/25.2, the C. elegans
homologs of the mammalian tumor suppressor kinase LKB1 and its binding
partners STRAD-alpha (608626) and MO25-alpha (612174). The AMPK-related
kinase Pig1, a possible target of the Par4-Strd1-Mop25 kinase complex,
is also required for cell shedding. Pig1 promotes shed cell detachment
by preventing the cell surface expression of cell adhesion molecules.
Denning et al. (2012) concluded that their findings revealed a mechanism
for apoptotic cell elimination that is fundamentally distinct from that
of canonical programmed cell death.

BIOCHEMICAL FEATURES

- Crystal Structure

Zeqiraj et al. (2009) described the structure of the core heterotrimeric
LKB1-STRAD-alpha-MO25-alpha (612174) complex, revealing an unusual
allosteric mechanism of LKB1 activation. STRAD-alpha adopts a closed
conformation typical of active protein kinases and binds LKB1 as a
pseudosubstrate. STRAD-alpha and MO25-alpha promote the active
conformation of LKB1, which is stabilized by MO25-alpha interacting with
the LKB1 activation loop. Zeqiraj et al. (2009) suggested that this
previously undescribed mechanism of kinase activation may be relevant to
understanding the evolution of other pseudokinases, and also commented
that the structure reveals how mutations found in Peutz-Jeghers (175200)
syndrome and in various sporadic cancers impair LKB1 function.

GENE STRUCTURE

Jenne et al. (1998) determined that the STK11 gene extends over 23 kb of
genomic DNA and is composed of 9 exons, which are transcribed in
telomere-to-centromere direction. The splice junctions of intron 2
deviate from the GT/AG rule with sequences indicative of a novel class
of highly unusual eukaryotic introns.

Smith et al. (1999) found that the mouse Lkb1 gene consists of 10 exons
covering approximately 15 kb.

MAPPING

At a distance of 190 kb proximal to marker D19S886 on chromosome
19p13.3, Jenne et al. (1998) identified the STK11 gene.

Smith et al. (1999) mapped the mouse Lkb1 gene to chromosome 10.

MOLECULAR GENETICS

Peutz-Jeghers syndrome (PJS; 175200) is an autosomal dominant disorder
characterized by melanocytic macules of the lips, buccal mucosa, and
digits, multiple gastrointestinal hamartomatous polyps, and an increased
risk of various neoplasms. Jenne et al. (1998) performed mutation
analysis in 5 unrelated PJS patients and found mutations in STK11 in
each. The finding of a rearrangement on initial mutation screening in a
3-generation PJS family focused interest on STK11. In this family,
affected members carried an STK11 allele with a deletion of exons 4 and
5 and an inversion of exons 6 and 7 (602216.0001). In 4 other unrelated
PJS patients, they found 3 nonsense mutations (602216.0002, 602216.0003,
602216.0004) and 1 acceptor splice site mutation (602216.0005). All 5
germline mutations were predicted to disrupt the function of the kinase
domain. Jenne et al. (1998) concluded that germline mutations in STK11,
probably in conjunction with acquired genetic defects of the second
allele in somatic cells according to the Knudson model, caused the
manifestations of PJS.

Hemminki et al. (1998) identified STK11, the gene on 19q mutant in
individuals affected by PJS, as a previously unpublished anonymous cDNA
clone in GenBank, LKB1, which showed strong homology to a cytoplasmic
serine/threonine protein kinase in Xenopus, XEEK1 (Su et al., 1996), and
weaker similarity to many other protein kinases. They found mutations in
the STK11 gene in 11 of 12 unrelated families with PJS. Ten of the 11
were truncating mutations. All were heterozygous in the germline.
Hemminki et al. (1998) commented that PJS was the first cancer
susceptibility syndrome identified that is due to inactivating mutations
in a protein kinase. Activation of kinase activity may be responsible
for cancer susceptibility in multiple endocrine neoplasia type II
(164761), familial renal papillary cancer (164860), and familial
melanoma (155600).

In 2 Indian families, Mehenni et al. (1998) could find no mutations in
the STK11 gene in patients with PJS; in 1 of these families they had
previously detected linkage to markers on 19q13.3-q13.4.

To investigate the prevalence of STK11 germline mutations in PJS,
Ylikorkala et al. (1999) studied samples from 33 unrelated PJS patients,
including 8 nonfamilial sporadic patients, 20 familial patients, and 5
patients with unknown family history. They identified 19 germline
mutations, 12 (60%) in familial and 4 (50%) in sporadic cases. STK11
mutations were not detected in 14 (42%) patients, indicating that the
existence of additional minor PJS loci cannot be excluded. To
demonstrate the putative STK11 kinase function and to study the
consequences of STK11 mutations in PJS and sporadic tumors, Ylikorkala
et al. (1999) analyzed the kinase activity of wildtype and mutant STK11
proteins. Whereas most of the small deletions or missense mutations
resulted in loss-of-function alleles, 1 missense mutation (gly163 to
asp; 602216.0011), previously identified in a sporadic testicular tumor
(Avizienyte et al., 1998), demonstrated severely impaired but detectable
kinase activity.

A teenaged girl with Peutz-Jeghers syndrome described as case 7 by
Jeghers et al. (1949) died of pancreatic cancer in her early thirties.
Guldberg et al. (1999) were prompted to search for STK11 somatic
mutations in malignant melanomas because of the lentigines of the lips
and oral mucosa that represent a cardinal feature of Peutz-Jeghers
syndrome. In a study of cell lines in tumor samples from 35 patients
with sporadic malignant melanoma, they identified 2 somatic mutations: a
nonsense mutation (glu170 to ter; 602216.0018) causing exon skipping and
intron retention, and a missense mutation (asp194 to tyr; 602216.0013)
affecting an invariant residue in the catalytic subunit of STK11. Rowan
et al. (1999) likewise postulated that the melanin spots of PJS patients
are small benign tumors and that if mutations provide these lesions with
a selective advantage, similar mutations might give a selective
advantage to related malignant tumors, such as melanomas. Among 16
melanoma cell lines, 15 primary melanomas, and 19 metastases, Rowan et
al. (1999) found 2 somatic mutations: a missense change (tyr49 to asp;
602216.0019) accompanied by allele loss in a cell line; and a missense
change (gly135 to arg; 602216.0020), without a detected mutation in the
other allele, in a primary tumor. They suspected both of these mutations
to be pathogenic.

Su et al. (1999) found that of 53 PJS patients with cancer reported to
that time, 6 (11%) were diagnosed with pancreatic adenocarcinoma,
including case 7 in the report by Jeghers et al. (1949). Su et al.
(1999) presented evidence that the STK11 gene plays a role in the
development of both sporadic and familial (PJS) pancreatic and biliary
cancers. They found that in sporadic cancers, the STK11 gene was
somatically mutated in 5% of pancreatic cancers and in at least 6% of
biliary cancers examined. In the patient with pancreatic cancer
associated with PJS, there was inheritance of a mutated copy of the
STK11 gene and somatic loss of the remaining wildtype allele.

When the syndromal association of melanin spots and intestinal polyps
was first described, Jeghers et al. (1949) pointed out that it
presumably reflected the pleiotropic effects of a single gene, not a
syndrome due to closely linked genes of the sort that were later
designated contiguous gene syndromes by Schmickel (1986). This was
concluded on the basis of genetic principles, since even closely linked
genes can get separated from each other. The mechanism of the
pleiotropism was, however, unclear. Now that the polyps in the
Peutz-Jeghers syndrome are known to be caused by a Knudson 2-hit
mechanism, the melanin spots presumably represent a similar 2-hit
mutation in melanoblasts, giving a spotted result. The reason for the
characteristic location of the pigmented spots, like the reason for the
predominant location of the intestinal polyps in the jejunum, is
unclear. In the perioral and buccal areas and the intestine, there may
be particular mutation-inciting factors predisposing to the second
somatic 'hit.' Perhaps one such factor is pressure or irritation or some
other physical factor.

Westerman et al. (1999) found novel STK11 mutations in 12 of 19
predominantly Dutch families with PJS. No mutation was found in the
remaining 7 families. None of the mutations occurred in more than 1
family, and a number were demonstrated to have arisen de novo. The
likelihood of locus heterogeneity was raised.

Nezu et al. (1999) characterized the basic biochemical properties of
LKB1. By analysis of mutant LKB1 identified in PJS patients, they found
that 1 of the mutants, SL26, a small in-frame deletion, did not lose its
kinase function but altered its subcellular distribution to accumulate
in the nucleus only, whereas wildtype LKB1 shows both nuclear and
cytoplasmic localization. Domain mapping of the nuclear targeting signal
of LKB1 assigned it to its N-terminal side. Furthermore, it was shown
that LKB1 also has a cytoplasmic retention ability that was defective
and pathogenic in the SL26 mutant. Nezu et al. (1999) speculated that
subcellular distribution of LKB1 is regulated in the balance of these 2
forces, importation into the nucleus and retention within the cytoplasm,
and that the cytoplasmic retention ability is necessary for LKB1 to
fulfill its normal function.

Since patients with PJS are at increased risk of benign and malignant
ovarian tumors, particularly granulosa cell tumors, and because loss of
heterozygosity (LOH) has been reported for 19p13.3 in about 50% of
ovarian cancers, Wang et al. (1999) screened 10 ovarian cancers with LOH
for chromosome 19, 35 other ovarian cancers, and 12 granulosa cell
tumors of the ovary for somatic mutations in the LKB1 gene. No variants
were detected in any of the adenocarcinomas. Two mutations, a missense
mutation affecting the putative start codon and a silent change in exon
7, were detected in 1 of the granulosa cell tumors. Like BRCA1 (113705)
and BRCA2 (600185), therefore, it appeared that LKB1 mutations can cause
ovarian tumors when present in the germline, but occur rarely as somatic
mutations causing sporadic tumors. Wang et al. (1999) concluded that the
allele loss at 19p13.3 in ovarian cancers almost certainly targets a
different gene from LKB1.

Abed et al. (2001) reported that mutation screening at the RNA level of
the STK11 gene in PJS revealed complex splicing abnormalities. They
suggested that since germinal mutations have been found in no more than
60% of cases, RNA-based screening procedures in peripheral blood cells
should be performed in cases of PJS where no mutations are identified at
the DNA level. They described a compound heterozygous PJS patient who
carried 2 different mutations in intron 1 of the STK11 gene on separate
alleles. Each of the 2 mutations was transmitted individually to 1 of
his 2 children; 1 of the children had spots on the lips, whereas the
other did not demonstrate lentigines of the lips and oral mucosa at the
age of 8 years.

In Australia, Scott et al. (2002) studied 5 unrelated probands and 9
unrelated patients with PJS for mutations in the STK11 gene. They
identified only 3 unequivocally causative mutations, 2 deletions and 1
splice site mutation, in 3 probands. Two missense mutations were
considered 'likely to be causative;' see 602216.0021. In a large
3-generation family, linkage analysis yielded a multipoint lod score of
4.5 with the STK11 region; however, no mutations were identified in the
coding region of the STK11 gene.

Amos et al. (2004) screened 42 independent probands for mutations in the
STK11 gene and detected mutations in 22 of 32 (69%) probands with PJS
and 0 of 10 probands referred to rule out PJS. In a total of 51
participants with PJS, the authors found gastric polyps to be very
common, with a median age at onset of 16 years. Individuals with
missense mutations had a significantly later time to onset of first
polypectomy (p = 0.04) and of other symptoms compared with those
participants with either truncating mutations or no detectable mutation.
Amos et al. (2004) concluded that STK11 mutation analysis should be
restricted to individuals who meet PJS criteria or their close
relatives.

Le Meur et al. (2004) reported a family with typical features of PJS,
including melanin spots of the oral mucosa, gastrointestinal
hamartomatous polyps, and breast and colon cancer. Using quantitative
multiplex PCR of short fluorescent fragments of the 19p13 region, they
identified an approximately 250-kb heterozygous deletion that completely
removed the STK11 locus. Le Meur et al. (2004) stated that this was the
first report of a complete germline deletion of STK11 and suggested that
the presence of such large genomic deletions should be considered in PJS
families without detectable point mutations of STK11.

In a study of 132 PJS patients with or without cancer who had mutations
in the STK11 gene, Schumacher et al. (2005) found that mutations in the
part of the gene involved in ATP binding and catalysis were rarely
associated with cancer, whereas mutations in the part of the gene
involved in substrate recognition were more frequently associated with
malignancies. PJS patients with breast cancers had predominantly
truncating mutations.

In a patient with PJS and a primary gastric cancer (see 137215),
Shinmura et al. (2005) identified heterozygosity for a germline deletion
mutation of the STK11 gene (602216.0022) encoding a truncated protein.
No inactivation of the wildtype allele by somatic mutation, chromosomal
deletion, or hypermethylation at the 5-prime CpG site of STK11 was
detected in the gastric carcinoma. The patient's sister also had PJS and
died of gastric carcinoma in her twenties. Shinmura et al. (2005) stated
that this was the first report of an STK11 germline mutation in a PJS
patient with gastric carcinoma.

Aretz et al. (2005) performed a mutation analysis of the STK11 gene in
71 patients, of whom 56 met the critical criteria for PJS and 12 were
presumed to have PJS because of mucocutaneous pigmentation only or bowel
problems due to isolated PJS-type polyps. No clinical information was
available for the remaining 3 patients. By direct sequencing of the
coding region of the STK11 gene, they identified point mutations in 37
(52%) of 71 patients. In the remaining 34 patients, the multiplex
ligation-dependent probe amplification (MLPA) method detected deletions
in 17 patients. In 4 patients the deletion extended over all 10 exons,
and in 8 patients only the promoter region in exon 1 was deleted. The
remaining deletions encompassed exons 2-10 (2 patients), exons 2-3,
exons 4-5, or exon 8 (1 patient, respectively). When only patients who
met the clinical criteria for PJS were considered, the overall mutation
detection rate increased to 94% (64% point mutations and 30% large
deletions). No mutation was identified in any of the 12 presumed cases.
Thus, they found that approximately one-third of the patients who met
the clinical PJS criteria exhibited large genomic deletions that were
readily detectable by MLPA. Since there may still be other mutations in
the STK11 gene that were not detectable by the methods used by Aretz et
al. (2005), they questioned whether a second PJS locus exists at all.

Forcet et al. (2005) investigated the functional consequences of LKB1
missense mutations (see, e.g., 602216.0024) in the C-terminal
noncatalytic region. C-terminal mutations did not disrupt LKB1 kinase
activity or interfere with LKB1-induced growth arrest; however, they
lessened LKB1-mediated activation of the AMP-activated protein kinase
(AMPK; 602739) and impaired downstream signaling. C-terminal mutations
compromised LKB1 ability to establish and maintain polarity of both
intestinal epithelial cells and migrating astrocytes. Mutation analysis
revealed that the LKB1 tail exerted an essential function in the control
of cell polarity. Forcet et al. (2005) proposed a crucial regulatory
role for the LKB1 C-terminal region, and suggested that LKB1 tumor
suppressor activity is likely to depend on the regulation of AMPK
signaling and cell polarization.

Chow et al. (2006) screened 33 PJS patients from unrelated families,
employing a combination of denaturing high-performance liquid
chromatography, direct DNA sequencing, and the multiplex ligation probe
amplification (MLPA) assay to identify deleterious changes in the STK11
gene. The results revealed that 24 (73%) of patients harbored pathogenic
mutations in the STK11 gene, including 10 (36%) with exonic or
whole-gene deletions. No phenotypic differences were identified in
patients harboring large deletions in the STK11 gene compared to
patients harboring missense or nonsense mutations. Chow et al. (2006)
concluded that most if not all PJS is attributable to mutations in the
STK11 gene, perhaps including undiscovered changes in promoter or
enhancer sequences or other cryptic changes.

ANIMAL MODEL

Ylikorkala et al. (2001) generated mice deficient in Lkb1 by targeted
disruption. Lkb1 -/- mice die at midgestation, with the embryos showing
neural tube defects, mesenchymal cell death, and vascular abnormalities.
Extraembryonic development was also severely affected; the mutant
placentas exhibited defective labyrinth-layer development and the fetal
vessels failed to invade the placenta. These phenotypes were associated
with tissue-specific deregulation of vascular endothelial growth factor
(VEGF; 192240) expression, including a marked increase in the amount of
VEGF mRNA. Moreover, VEGF production in cultured Lkb1 -/- fibroblasts
was elevated in both normoxic and hypoxic conditions. Ylikorkala et al.
(2001) concluded that their findings place Lkb1 in the VEGF signaling
pathway and suggested that vascular defects accompanying Lkb1 loss are
mediated at least in part by VEGF.

To investigate the role of LKB1 in PJS (175200) phenotypes, Miyoshi et
al. (2002) introduced a germline mutation in the mouse Lkb1 gene by
homologous recombination in mouse embryonic stem cells. In most
heterozygous mice over 20 weeks of age, hamartomatous polyps developed
in the glandular stomach, often in the pyloric region. Small intestinal
hamartomas also developed in approximately one-third of the heterozygous
mice over 50 weeks of age. Genomic PCR and sequence analysis showed that
all hamartomas retained both the wildtype and the targeted Lkb1 alleles,
indicating that allelic loss of the wildtype Lkb1 was not the cause of
polyp formation. Moreover, the Lkb1 protein level was not reduced in
hamartomatous polyps compared with that in Lkb1 heterozygous normal
gastric mucosa. In addition, the remaining allele showed no missense
mutations in the coding sequence and did not produce truncated LKB1 in
the hamartoma. Taken together, these data suggested that the wildtype
Lkb1 gene is expressed in the hamartoma at the haploid amount.
Accordingly, the gastrointestinal hamartomas appear to develop because
of Lkb1 haploinsufficiency. Although additional genetic events may be
critical in hamartoma and adenocarcinoma development, these data
strongly suggest that the initiation of polyposis is not the result of
loss of heterozygosity in Lkb1.

Jishage et al. (2002) constructed a knockout mutation of the Lkb1 gene
in mice to determine whether it is the causative gene of PJS and to
examine its biologic role. Homozygous-null mice died in utero between
8.5 and 9.5 days postcoitum. At 9.0 days postcoitum, null embryos were
generally smaller than their age-matched littermates, showed
developmental retardation, and did not undergo embryonic turning.
Multiple gastric adenomatous polyps were observed in 10- to 14-month-old
heterozygous mice. The results indicated that functional LKB1 is
required for normal embryogenesis and that it is related to tumor
development.

Bardeesy et al. (2002) generated Lkb1 knockout and heterozygous mice by
targeted disruption. Lkb1 heterozygotes developed intestinal polyps
identical to those seen in individuals affected with PJS. Consistent
with this in vivo tumor suppressor function, Lkb1 deficiency prevented
culture-induced senescence without loss of Ink4a/Arf (600160) or p53.
Despite compromised mortality, Lkb1 -/- mouse embryonic fibroblasts
showed resistance to transformation by activated Hras (190020) either
alone or with immortalizing oncogenes. This phenotype is in agreement
with the paucity of mutations in Ras seen in PJS polyps and suggests
that loss of LKB1 function as an early neoplastic event renders cells
resistant to subsequent oncogene-induced transformation. In addition,
the Lkb1 transcriptome showed modulation of factors linked to
angiogenesis, extracellular matrix remodeling, cell adhesion, and
inhibition of Ras transformation. Bardeesy et al. (2002) concluded that
taken together, their data rationalized several features of PJS
polyposis, notably its peculiar histopathologic presentation and limited
malignant potential, and placed Lkb1 in a distinct class of tumor
suppressors.

Rossi et al. (2002) generated mice heterozygous for a targeted
inactivating allele of Lkb1. The mice developed severe gastrointestinal
polyposis. The polyps were hamartomas histologically indistinguishable
from polyps resected from PJS patients, indicating that Lkb1
heterozygous mice model human PJS polyposis. There was no evidence of
inactivation of the remaining wildtype Lkb1 allele in Lkb1
heterozygous-associated polyps. Moreover, polyps and other tissues in
heterozygote animals exhibited reduced Lkb1 levels and activity,
indicating that Lkb1 was haploinsufficient for tumor suppression.
Analysis of the molecular mechanisms characterizing Lkb1 heterozygous
polyposis revealed that cyclooxygenase-2 (COX2; 600262) was highly
upregulated in mouse polyps concomitantly with activation of the
extracellular signal-regulated kinases 1 (ERK1; 601795) and 2 (ERK2;
176948). COX2 was also highly upregulated in most of a large series of
human PJS polyps subsequently examined. These findings thereby
identified COX2 as a potential target for chemoprevention in PJS
patients.

Shaw et al. (2005) created conditional knockout mice in which Lkb1 was
deleted in adult liver only. These mice showed nearly complete loss of
adenosine monophosphate (AMP)-activated protein kinase (AMPK; see
600497) activity. Loss of Lkb1 function resulted in hyperglycemia with
increased gluconeogenic and lipogenic gene expression. In Lkb1-deficient
livers, Torc2 (608972), a transcriptional coactivator of CREB (123810),
was dephosphorylated and entered the nucleus, driving the expression of
PPAR-gamma coactivator 1-alpha (PGC1A; 604517), which in turn drives
gluconeogenesis. Adenoviral small hairpin RNA for Torc2 reduced Pgc1a
expression and normalized blood glucose levels in mice with deleted
liver Lkb1, indicating that TORC2 is a critical target of LKB1-AMPK
signals in the regulation of gluconeogenesis. Finally, Shaw et al.
(2005) showed that metformin, a widely prescribed type 2 diabetes
therapy, requires LKB1 in the liver to lower blood glucose levels.

HISTORY

Lin et al. (2012) reported that acetylation and deacetylation of the
catalytic subunit of the adenosine monophosphate-activated protein
kinase (AMPK), PRKAA1 (602739), a critical cellular energy-sensing
protein kinase complex, is controlled by the opposing catalytic
activities of HDAC1 (601241) and p300. Deacetylation of AMPK enhanced
physical interaction with the upstream kinase LKB1 (602216), leading to
AMPK phosphorylation and activation, and resulting in lipid breakdown in
human liver cells. The authors later found that the Methods section of
their article was inaccurate. Because they could not reproduce all of
their results, they retracted the article.

*FIELD* AV
.0001
PEUTZ-JEGHERS SYNDROME
STK11, EX4-5DEL/EX6-7INV

In a 3-generation family, Jenne et al. (1998) found that members with
Peutz-Jeghers syndrome (PJS; 175200) were heterozygous for a deletion of
exons 4 and 5 and an inversion of exons 6 and 7 in the STK11 gene. Codon
155 was the last wildtype codon and codons 156 through 307 were deleted.

.0002
PEUTZ-JEGHERS SYNDROME
STK11, TYR253TER

In a patient with PJS (175200), Jenne et al. (1998) identified a
heterozygous 759C-A transversion, resulting in a change of codon 253
from TAC (tyr) to TAA (stop) (Y253X). The last wildtype codon was number
252 in exon 6.

.0003
PEUTZ-JEGHERS SYNDROME
STK11, 1-BP DEL, 843G

In a patient with PJS (175200), Jenne et al. (1998) found that the STK11
gene carried a heterozygous deletion of nucleotide 843G, resulting in
frameshift and stop at codon 286. Codon 280 was the last wildtype codon.

.0004
PEUTZ-JEGHERS SYNDROME
STK11, 4-BP DEL, 716GGTC

In a patient with PJS (175200), Jenne et al. (1998) identified a
heterozygous 4-bp deletion (716delGGTC) in exon 5 of the STK11 gene. The
deletion caused a frameshift with a stop at codon 285; the last wildtype
codon was 240.

.0005
PEUTZ-JEGHERS SYNDROME
STK11, IVS3, G-A, -1

In a patient with PJS (175200), Jenne et al. (1998) identified a
heterozygous splice site mutation that changed the strictly conserved
splice acceptor site at the 3-prime end of intron 3 from AG to AA.
Because mRNA was not available from this patient, Jenne et al. (1998)
could not demonstrate the most likely consequence of this mutation, the
joining of exon 3 with exon 5, which would result in a reading
frameshift after residue 155 and subsequent termination of the altered
protein sequence after residue 241.

.0006
PEUTZ-JEGHERS SYNDROME
STK11, LYS84TER

In their patient SL32 with PJS (175200), Hemminki et al. (1998)
identified a heterozygous lys84-to-ter mutation (K84X) in the STK11
gene.

.0007
PEUTZ-JEGHERS SYNDROME
STK11, 2-BP DEL, NT277

In their patient SL31 with PJS (175200), Hemminki et al. (1998) found a
heterozygous deletion of nucleotides 277 and 278 of the STK11 mRNA
causing frameshift and premature termination at codon 283.

.0008
PEUTZ-JEGHERS SYNDROME
STK11, LEU67PRO

In 1 of their 12 families with PJS (175200), Hemminki et al. (1998)
found a heterozygous T-to-C transition in the STK11 gene, resulting in a
leu67-to-pro (L67P) substitution.

.0009
PEUTZ-JEGHERS SYNDROME
STK11, 9-BP DEL

In their patient SL26 with PJS (175200), Hemminki et al. (1998)
identified a heterozygous 9-bp deletion, converting 4 codons (303 to
306) from ile-arg-gln-his to asn.

.0010
PEUTZ-JEGHERS SYNDROME
STK11, GLU57TER

In their patient SL12 with PJS (175200), Hemminki et al. (1998) found a
heterozygous glu57-to-ter (E57X) nonsense mutation in the STK11 gene.

.0011
TESTICULAR TUMOR, SOMATIC
STK11, GLY163ASP

Avizienyte et al. (1998) identified a somatic gly163-to-asp mutation of
the STK11 gene in a case of sporadic testicular carcinoma (273300). In
further studies, Ylikorkala et al. (1999) found that this mutation was
associated with severely impaired but detectable kinase activity.

.0012
PEUTZ-JEGHERS SYNDROME
STK11, 1-BP DEL, 1407C

In the family with Peutz-Jeghers syndrome (175200) originally studied by
McKusick, who contributed to the publication of Jeghers et al. (1949),
Gruber et al. (1998) found linkage to 19p13.3. By sequencing genomic DNA
they identified a 1407delC germline mutation in the STK11 gene. Three
affected family members were found to be heterozygous for the mutation,
and 3 unaffected individuals carried 2 wildtype alleles.

.0013
MELANOMA, MALIGNANT, SOMATIC
STK11, ASP194TYR

In a sample of cell lines and tumor specimens from 35 patients with
sporadic malignant melanoma (see 155600), Guldberg et al. (1999)
identified 2 somatic mutations, 1 of which, an asp194-to-tyr
substitution, affected an invariant residue in the catalytic subunit of
STK11.

.0014
PEUTZ-JEGHERS SYNDROME
STK11, 1-BP INS, 535T

In the Dutch family in which Peutz (1921) first described the
association of gastrointestinal polyps with mucocutaneous melanin spots,
now known as Peutz-Jeghers syndrome (175200), Westerman et al. (1999)
found that affected individuals were heterozygous for a T insertion at
nucleotide 535 in codon 66 of the STK11 gene, resulting in a frameshift
that produced a stop signal at codon 162 in exon 4. All affected
patients, but none of their unaffected relatives, carried this mutation.

.0015
PANCREATIC CANCER, SOMATIC
STK11, TYR36TER

In a series of pancreatic cancers with loss of heterozygosity (LOH), Su
et al. (1999) found that 3 had mutations in the STK11 gene: 1 nonsense
and 2 frameshift mutations. The nonsense mutation, tyr36 to ter, which
occurred in exon 1, and 1 of the frameshift mutations (602216.0016),
which occurred in exon 5, were within the catalytic kinase domain of
STK11 (codons 37 to 314).

.0016
PANCREATIC CANCER, SOMATIC
STK11, 1-BP DEL, CODON 217

In a pancreatic cancer that showed loss of heterozygosity of 1 allele in
the 19p13.3 region, Su et al. (1999) found that the other allele carried
somatic deletion of a cytosine in codon 217 in exon 5, converting CCG to
CGG and causing a frameshift.

.0017
PANCREATIC CANCER, SOMATIC
STK11, 1-BP DEL, CODON 312

In a pancreatic cancer that showed loss of heterozygosity of 1 allele in
the 19p13.3 region, Su et al. (1999) found that the other allele carried
a somatic deletion of an adenine in codon 312 of exon 8, converting AAA
to AAC and causing a frameshift. This mutation would potentially affect
the function of the regulatory domain of STK1 that comprises the 119
residues at the C terminus.

.0018
MELANOMA, MALIGNANT, SOMATIC
STK11, GLU170TER

In a cell line prepared from a tumor in a patient with sporadic melanoma
(see 155600), Guldberg et al. (1999) identified a glu170-to-ter mutation
causing exon skipping and intron retention.

.0019
MELANOMA, MALIGNANT, SOMATIC
STK11, TYR49ASP

In a melanoma cell line derived from a primary lesion (see 155600),
Rowan et al. (1999) found a tyr49-to-asp (Y49D) missense mutation in the
STK11 gene product. No wildtype STK11 allele was detected on sequencing,
strongly suggesting mutation of the other allele by loss of
heterozygosity (LOH).

.0020
MELANOMA, MALIGNANT, SOMATIC
STK11, GLY135ARG

In a primary melanoma (see 155600), Rowan et al. (1999) found a somatic
gly135-to-arg (G135R) missense change in the STK11 protein. The mutation
was found in heterozygous state.

.0021
PEUTZ-JEGHERS SYNDROME
STK11, TRP239CYS

In an Australian patient diagnosed with Peutz-Jeghers syndrome (175200)
at the age of 42 years, Scott et al. (2002) identified a heterozygous
717G-C transversion in exon 5 of the STK11 gene, resulting in a
trp239-to-cys (W239C) substitution. Although the features of
Peutz-Jeghers syndrome were typical, the late onset suggested reduced
penetrance.

.0022
PEUTZ-JEGHERS SYNDROME
STK11, 1-BP DEL, 890G

In a patient with PJS (175200) and a primary gastric cancer (137215),
Shinmura et al. (2005) identified heterozygosity for an 890G deletion in
exon 7 of the STK11 gene, resulting in a frameshift at codon arg297, the
introduction of 38 novel amino acids, and premature truncation at 334
amino acids. No inactivation of the wildtype allele by somatic mutation,
chromosomal deletion, or hypermethylation at the 5-prime CpG site of
STK11 was detected in the gastric carcinoma. The patient's sister also
had PJS and died of gastric carcinoma in her twenties. Shinmura et al.
(2005) stated that this was the first report of an STK11 germline
mutation in a PJS patient with gastric carcinoma.

.0023
PEUTZ-JEGHERS SYNDROME
STK11, TYR246TER

In a 20-year-old female patient with PJS (175200) and gastrointestinal
hamartomatous polyps, Hernan et al. (2004) identified a de novo
heterozygous germline 3256C-G transversion in exon 6 of the STK11 gene,
resulting in a tyr246-to-ter (Y246X) substitution, predicted to cause
truncation of the protein. This mutation was not found in her parents.
Comparison of melting curve profiles obtained from DNA from the
patient's lymphocytes and hamartomatous polyps showed no differences,
indicative of a heterozygous mutation rather than loss of heterozygosity
in the polyps. Hernan et al. (2004) suggested that biallelic
inactivation of STK11 is not necessarily required for hamartoma
formation in PJS patients.

.0024
PEUTZ-JEGHERS SYNDROME
STK11, PHE354LEU

In a 14-year-old proband with PJS (175200), Forcet et al. (2005)
identified a heterozygous C-to-G transversion in exon 8 of the STK11
gene, resulting in a phe354-to-leu (F354L) substitution. The proband
displayed a large number of pigmented macules without evidence of
intestinal polyps. The proband's mother, who transmitted the germline
mutation, was asymptomatic.

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*FIELD* CN
Ada Hamosh - updated: 8/28/2012
Ada Hamosh - updated: 3/7/2012
Ada Hamosh - updated: 7/1/2011
Patricia A. Hartz - updated: 2/16/2011
Ada Hamosh - updated: 1/25/2011
Ada Hamosh - updated: 1/8/2010
George E. Tiller - updated: 11/20/2008
George E. Tiller - updated: 5/30/2008
Ada Hamosh - updated: 5/7/2008
Ada Hamosh - updated: 10/15/2007
Victor A. McKusick - updated: 9/4/2007
Ada Hamosh - updated: 4/18/2006
Victor A. McKusick - updated: 1/6/2006
Marla J. F. O'Neill - updated: 8/4/2005
Marla J. F. O'Neill - updated: 6/20/2005
Marla J. F. O'Neill - updated: 3/1/2005
Marla J. F. O'Neill - updated: 6/11/2004
Marla J. F. O'Neill - updated: 6/2/2004
Stylianos E. Antonarakis - updated: 5/3/2004
Stylianos E. Antonarakis - updated: 4/29/2004
Victor A. McKusick - updated: 1/15/2004
George E. Tiller - updated: 5/28/2003
Ada Hamosh - updated: 2/3/2003
Victor A. McKusick - updated: 11/6/2002
Victor A. McKusick - updated: 10/21/2002
Ada Hamosh - updated: 9/30/2002
George E. Tiller - updated: 9/9/2002
Victor A. McKusick - updated: 8/26/2002
Victor A. McKusick - updated: 8/9/2002
Victor A. McKusick - updated: 11/29/2001
Ada Hamosh - updated: 8/27/2001
Stylianos E. Antonarakis - updated: 7/3/2001
Victor A. McKusick - updated: 10/28/1999
Victor A. McKusick - updated: 9/29/1999
Victor A. McKusick - updated: 8/13/1999
Victor A. McKusick - updated: 6/8/1999
Victor A. McKusick - updated: 5/12/1999
Victor A. McKusick - updated: 5/6/1999
Victor A. McKusick - updated: 2/18/1999
Victor A. McKusick - updated: 2/17/1999
Victor A. McKusick - updated: 12/18/1998
Victor A. McKusick - updated: 3/25/1998
Victor A. McKusick - edited: 1/29/1998
Victor A. McKusick - updated: 1/19/1998

*FIELD* CD
Victor A. McKusick: 12/29/1997

*FIELD* ED
carol: 11/07/2013
carol: 11/7/2013
carol: 10/28/2013
carol: 4/12/2013
joanna: 4/12/2013
carol: 12/20/2012
alopez: 8/29/2012
terry: 8/28/2012
alopez: 3/12/2012
terry: 3/7/2012
mgross: 8/25/2011
alopez: 7/7/2011
terry: 7/1/2011
terry: 4/7/2011
mgross: 2/16/2011
alopez: 2/1/2011
terry: 1/25/2011
alopez: 1/11/2010
terry: 1/8/2010
wwang: 11/20/2008
wwang: 6/3/2008
terry: 5/30/2008
alopez: 5/8/2008
terry: 5/7/2008
alopez: 10/26/2007
terry: 10/15/2007
alopez: 9/7/2007
terry: 9/4/2007
carol: 5/3/2007
alopez: 4/24/2006
terry: 4/18/2006
joanna: 3/21/2006
wwang: 1/12/2006
terry: 1/6/2006
wwang: 8/5/2005
terry: 8/4/2005
wwang: 6/22/2005
wwang: 6/20/2005
terry: 4/5/2005
wwang: 3/3/2005
terry: 3/1/2005
carol: 6/14/2004
terry: 6/11/2004
carol: 6/8/2004
terry: 6/2/2004
mgross: 5/3/2004
mgross: 4/29/2004
tkritzer: 1/29/2004
terry: 1/15/2004
cwells: 5/28/2003
alopez: 2/4/2003
terry: 2/3/2003
carol: 11/12/2002
tkritzer: 11/11/2002
terry: 11/6/2002
carol: 10/22/2002
tkritzer: 10/21/2002
alopez: 10/1/2002
tkritzer: 9/30/2002
cwells: 9/9/2002
tkritzer: 9/6/2002
tkritzer: 8/28/2002
terry: 8/26/2002
carol: 8/15/2002
tkritzer: 8/15/2002
tkritzer: 8/13/2002
terry: 8/9/2002
carol: 1/15/2002
mcapotos: 12/11/2001
terry: 11/29/2001
cwells: 8/29/2001
terry: 8/27/2001
mgross: 7/3/2001
mgross: 10/28/1999
mgross: 10/13/1999
terry: 9/29/1999
carol: 8/20/1999
terry: 8/13/1999
jlewis: 7/22/1999
joanna: 7/21/1999
alopez: 7/12/1999
terry: 6/8/1999
mgross: 5/19/1999
carol: 5/19/1999
mgross: 5/17/1999
terry: 5/12/1999
terry: 5/6/1999
mgross: 3/10/1999
mgross: 2/24/1999
mgross: 2/19/1999
mgross: 2/18/1999
terry: 2/17/1999
carol: 12/29/1998
terry: 12/23/1998
terry: 12/18/1998
alopez: 11/3/1998
terry: 3/25/1998
terry: 3/2/1998
mark: 1/29/1998
terry: 1/28/1998
dholmes: 1/26/1998
mark: 1/19/1998
terry: 1/19/1998
terry: 12/29/1997
alopez: 12/23/1997

RBCC Red Blood Cell Collection

Full text data of STK11