Full text data of RRAS2
RRAS2
(TC21)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ras-related protein R-Ras2 (Ras-like protein TC21; Teratocarcinoma oncogene; Flags: Precursor)
Ras-related protein R-Ras2 (Ras-like protein TC21; Teratocarcinoma oncogene; Flags: Precursor)
UniProt
P62070
ID RRAS2_HUMAN Reviewed; 204 AA.
AC P62070; B2R9Z3; B7Z6C4; B7Z7H6; P17082;
DT 21-JUN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUN-2004, sequence version 1.
DT 22-JAN-2014, entry version 115.
DE RecName: Full=Ras-related protein R-Ras2;
DE AltName: Full=Ras-like protein TC21;
DE AltName: Full=Teratocarcinoma oncogene;
DE Flags: Precursor;
GN Name=RRAS2; Synonyms=TC21;
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] (ISOFORM 1).
RX PubMed=2108320;
RA Drivas G.T., Shih A., Coutavas E., Rush M.G., D'Eustachio P.;
RT "Characterization of four novel ras-like genes expressed in a human
RT teratocarcinoma cell line.";
RL Mol. Cell. Biol. 10:1793-1798(1990).
RN [2]
RP SEQUENCE REVISION TO 5-11, TISSUE SPECIFICITY, AND VARIANT OVARIAN
RP CANCER LEU-72.
RX PubMed=8052619; DOI=10.1073/pnas.91.16.7558;
RA Chan A.M.-L., Miki T., Meyers K.A., Aaronson S.A.;
RT "A human oncogene of the RAS superfamily unmasked by expression cDNA
RT cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:7558-7562(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Pericardium, and Uterus;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone;
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 [8]
RP ISOPRENYLATION AT CYS-201.
RX PubMed=15308774; DOI=10.1073/pnas.0403413101;
RA Kho Y., Kim S.C., Jiang C., Barma D., Kwon S.W., Cheng J.,
RA Jaunbergs J., Weinbaum C., Tamanoi F., Falck J., Zhao Y.;
RT "A tagging-via-substrate technology for detection and proteomics of
RT farnesylated proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:12479-12484(2004).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
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 [16]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 10-181 IN COMPLEX WITH GDP.
RG Structural genomics consortium (SGC);
RT "The crystal structure of the Ras related protein RRAS2 in the GDP
RT bound state.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: It is a plasma membrane-associated GTP-binding protein
CC with GTPase activity. Might transduce growth inhibitory signals
CC across the cell membrane, exerting its effect through an effector
CC shared with the Ras proteins but in an antagonistic fashion.
CC -!- INTERACTION:
CC P10398:ARAF; NbExp=3; IntAct=EBI-491037, EBI-365961;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic
CC side (By similarity). Note=Inner surface of plasma membrane
CC possibly with attachment requiring acylation of the C-terminal
CC cysteine (By similarity with RAS).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P62070-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P62070-2; Sequence=VSP_043066;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P62070-3; Sequence=VSP_044485;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitously present in all tissues examined,
CC with the highest levels in heart, placenta, and skeletal muscle.
CC Moderate levels in lung and liver; low levels in brain, kidney,
CC and pancreas.
CC -!- PTM: May be post-translationally modified by both palmitoylation
CC and polyisoprenylation.
CC -!- DISEASE: Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer
CC defines malignancies originating from ovarian tissue. Although
CC many histologic types of ovarian tumors have been described,
CC epithelial ovarian carcinoma is the most common form. Ovarian
CC cancers are often asymptomatic and the recognized signs and
CC symptoms, even of late-stage disease, are vague. Consequently,
CC most patients are diagnosed with advanced disease. Note=Disease
CC susceptibility is associated with variations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA36545.1; Type=Frameshift; Positions=4, 8, 12;
CC Sequence=AAM12638.1; Type=Frameshift; Positions=4, 8, 12;
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DR EMBL; M31468; AAA36545.1; ALT_FRAME; mRNA.
DR EMBL; AF493924; AAM12638.1; ALT_FRAME; mRNA.
DR EMBL; AK300103; BAH13210.1; -; mRNA.
DR EMBL; AK302033; BAH13612.1; -; mRNA.
DR EMBL; AK313976; BAG36690.1; -; mRNA.
DR EMBL; AC011084; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471064; EAW68487.1; -; Genomic_DNA.
DR EMBL; BC013106; AAH13106.1; -; mRNA.
DR PIR; B34788; TVHUC2.
DR RefSeq; NP_001096139.1; NM_001102669.2.
DR RefSeq; NP_001170785.1; NM_001177314.1.
DR RefSeq; NP_001170786.1; NM_001177315.1.
DR RefSeq; NP_036382.2; NM_012250.5.
DR UniGene; Hs.502004; -.
DR UniGene; Hs.712835; -.
DR PDB; 2ERY; X-ray; 1.70 A; A/B=12-181.
DR PDBsum; 2ERY; -.
DR ProteinModelPortal; P62070; -.
DR SMR; P62070; 13-181.
DR IntAct; P62070; 14.
DR MINT; MINT-5001153; -.
DR STRING; 9606.ENSP00000256196; -.
DR PhosphoSite; P62070; -.
DR DMDM; 49065833; -.
DR PaxDb; P62070; -.
DR PeptideAtlas; P62070; -.
DR PRIDE; P62070; -.
DR DNASU; 22800; -.
DR Ensembl; ENST00000256196; ENSP00000256196; ENSG00000133818.
DR Ensembl; ENST00000414023; ENSP00000403282; ENSG00000133818.
DR Ensembl; ENST00000526063; ENSP00000434104; ENSG00000133818.
DR Ensembl; ENST00000529237; ENSP00000433230; ENSG00000133818.
DR Ensembl; ENST00000532814; ENSP00000431954; ENSG00000133818.
DR Ensembl; ENST00000534746; ENSP00000437083; ENSG00000133818.
DR Ensembl; ENST00000537760; ENSP00000437547; ENSG00000133818.
DR Ensembl; ENST00000571727; ENSP00000460749; ENSG00000262489.
DR Ensembl; ENST00000572201; ENSP00000460504; ENSG00000262489.
DR Ensembl; ENST00000572397; ENSP00000459423; ENSG00000262489.
DR Ensembl; ENST00000572894; ENSP00000458232; ENSG00000262489.
DR Ensembl; ENST00000573870; ENSP00000458679; ENSG00000262489.
DR Ensembl; ENST00000574530; ENSP00000460998; ENSG00000262489.
DR GeneID; 22800; -.
DR KEGG; hsa:22800; -.
DR UCSC; uc001mlf.4; human.
DR CTD; 22800; -.
DR GeneCards; GC11M014299; -.
DR HGNC; HGNC:17271; RRAS2.
DR HPA; CAB010420; -.
DR MIM; 167000; phenotype.
DR MIM; 600098; gene.
DR neXtProt; NX_P62070; -.
DR PharmGKB; PA34862; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P62070; -.
DR KO; K07830; -.
DR OMA; XKFQEQE; -.
DR PhylomeDB; P62070; -.
DR SignaLink; P62070; -.
DR EvolutionaryTrace; P62070; -.
DR GeneWiki; RRAS2; -.
DR GenomeRNAi; 22800; -.
DR NextBio; 43146; -.
DR PRO; PR:P62070; -.
DR ArrayExpress; P62070; -.
DR Bgee; P62070; -.
DR CleanEx; HS_RRAS2; -.
DR Genevestigator; P62070; -.
DR GO; GO:0005783; C:endoplasmic reticulum; NAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; NAS:ProtInc.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; TAS:ProtInc.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; IEA:Ensembl.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00173; RAS; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell membrane;
KW Complete proteome; Disease mutation; GTP-binding; Lipoprotein;
KW Membrane; Methylation; Nucleotide-binding; Palmitate; Phosphoprotein;
KW Prenylation; Proto-oncogene; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 201 Ras-related protein R-Ras2.
FT /FTId=PRO_0000082652.
FT PROPEP 202 204 Removed in mature form (By similarity).
FT /FTId=PRO_0000281302.
FT NP_BIND 21 29 GTP.
FT NP_BIND 68 72 GTP (By similarity).
FT NP_BIND 127 130 GTP.
FT NP_BIND 157 159 GTP.
FT MOTIF 43 51 Effector region.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 186 186 Phosphoserine.
FT MOD_RES 201 201 Cysteine methyl ester (Probable).
FT LIPID 199 199 S-palmitoyl cysteine (Potential).
FT LIPID 201 201 S-farnesyl cysteine.
FT VAR_SEQ 1 77 Missing (in isoform 2).
FT /FTId=VSP_043066.
FT VAR_SEQ 1 36 MAAAGWRDGSGQEKYRLVVVGGGGVGKSALTIQFIQ -> M
FT (in isoform 3).
FT /FTId=VSP_044485.
FT VARIANT 72 72 Q -> L (in an ovarian cancer sample;
FT somatic mutation).
FT /FTId=VAR_006848.
FT STRAND 14 21
FT HELIX 27 36
FT STRAND 49 57
FT STRAND 60 68
FT HELIX 77 85
FT STRAND 87 94
FT HELIX 98 102
FT HELIX 104 115
FT STRAND 121 127
FT HELIX 139 148
FT STRAND 152 155
FT TURN 158 161
FT HELIX 164 178
SQ SEQUENCE 204 AA; 23400 MW; BA7D4759DC49446F CRC64;
MAAAGWRDGS GQEKYRLVVV GGGGVGKSAL TIQFIQSYFV TDYDPTIEDS YTKQCVIDDR
AARLDILDTA GQEEFGAMRE QYMRTGEGFL LVFSVTDRGS FEEIYKFQRQ ILRVKDRDEF
PMILIGNKAD LDHQRQVTQE EGQQLARQLK VTYMEASAKI RMNVDQAFHE LVRVIRKFQE
QECPPSPEPT RKEKDKKGCH CVIF
//
ID RRAS2_HUMAN Reviewed; 204 AA.
AC P62070; B2R9Z3; B7Z6C4; B7Z7H6; P17082;
DT 21-JUN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 21-JUN-2004, sequence version 1.
DT 22-JAN-2014, entry version 115.
DE RecName: Full=Ras-related protein R-Ras2;
DE AltName: Full=Ras-like protein TC21;
DE AltName: Full=Teratocarcinoma oncogene;
DE Flags: Precursor;
GN Name=RRAS2; Synonyms=TC21;
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] (ISOFORM 1).
RX PubMed=2108320;
RA Drivas G.T., Shih A., Coutavas E., Rush M.G., D'Eustachio P.;
RT "Characterization of four novel ras-like genes expressed in a human
RT teratocarcinoma cell line.";
RL Mol. Cell. Biol. 10:1793-1798(1990).
RN [2]
RP SEQUENCE REVISION TO 5-11, TISSUE SPECIFICITY, AND VARIANT OVARIAN
RP CANCER LEU-72.
RX PubMed=8052619; DOI=10.1073/pnas.91.16.7558;
RA Chan A.M.-L., Miki T., Meyers K.A., Aaronson S.A.;
RT "A human oncogene of the RAS superfamily unmasked by expression cDNA
RT cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:7558-7562(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Pericardium, and Uterus;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone;
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 [8]
RP ISOPRENYLATION AT CYS-201.
RX PubMed=15308774; DOI=10.1073/pnas.0403413101;
RA Kho Y., Kim S.C., Jiang C., Barma D., Kwon S.W., Cheng J.,
RA Jaunbergs J., Weinbaum C., Tamanoi F., Falck J., Zhao Y.;
RT "A tagging-via-substrate technology for detection and proteomics of
RT farnesylated proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:12479-12484(2004).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
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 [16]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 10-181 IN COMPLEX WITH GDP.
RG Structural genomics consortium (SGC);
RT "The crystal structure of the Ras related protein RRAS2 in the GDP
RT bound state.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: It is a plasma membrane-associated GTP-binding protein
CC with GTPase activity. Might transduce growth inhibitory signals
CC across the cell membrane, exerting its effect through an effector
CC shared with the Ras proteins but in an antagonistic fashion.
CC -!- INTERACTION:
CC P10398:ARAF; NbExp=3; IntAct=EBI-491037, EBI-365961;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic
CC side (By similarity). Note=Inner surface of plasma membrane
CC possibly with attachment requiring acylation of the C-terminal
CC cysteine (By similarity with RAS).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P62070-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P62070-2; Sequence=VSP_043066;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P62070-3; Sequence=VSP_044485;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitously present in all tissues examined,
CC with the highest levels in heart, placenta, and skeletal muscle.
CC Moderate levels in lung and liver; low levels in brain, kidney,
CC and pancreas.
CC -!- PTM: May be post-translationally modified by both palmitoylation
CC and polyisoprenylation.
CC -!- DISEASE: Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer
CC defines malignancies originating from ovarian tissue. Although
CC many histologic types of ovarian tumors have been described,
CC epithelial ovarian carcinoma is the most common form. Ovarian
CC cancers are often asymptomatic and the recognized signs and
CC symptoms, even of late-stage disease, are vague. Consequently,
CC most patients are diagnosed with advanced disease. Note=Disease
CC susceptibility is associated with variations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Ras family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA36545.1; Type=Frameshift; Positions=4, 8, 12;
CC Sequence=AAM12638.1; Type=Frameshift; Positions=4, 8, 12;
CC -----------------------------------------------------------------------
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DR EMBL; M31468; AAA36545.1; ALT_FRAME; mRNA.
DR EMBL; AF493924; AAM12638.1; ALT_FRAME; mRNA.
DR EMBL; AK300103; BAH13210.1; -; mRNA.
DR EMBL; AK302033; BAH13612.1; -; mRNA.
DR EMBL; AK313976; BAG36690.1; -; mRNA.
DR EMBL; AC011084; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471064; EAW68487.1; -; Genomic_DNA.
DR EMBL; BC013106; AAH13106.1; -; mRNA.
DR PIR; B34788; TVHUC2.
DR RefSeq; NP_001096139.1; NM_001102669.2.
DR RefSeq; NP_001170785.1; NM_001177314.1.
DR RefSeq; NP_001170786.1; NM_001177315.1.
DR RefSeq; NP_036382.2; NM_012250.5.
DR UniGene; Hs.502004; -.
DR UniGene; Hs.712835; -.
DR PDB; 2ERY; X-ray; 1.70 A; A/B=12-181.
DR PDBsum; 2ERY; -.
DR ProteinModelPortal; P62070; -.
DR SMR; P62070; 13-181.
DR IntAct; P62070; 14.
DR MINT; MINT-5001153; -.
DR STRING; 9606.ENSP00000256196; -.
DR PhosphoSite; P62070; -.
DR DMDM; 49065833; -.
DR PaxDb; P62070; -.
DR PeptideAtlas; P62070; -.
DR PRIDE; P62070; -.
DR DNASU; 22800; -.
DR Ensembl; ENST00000256196; ENSP00000256196; ENSG00000133818.
DR Ensembl; ENST00000414023; ENSP00000403282; ENSG00000133818.
DR Ensembl; ENST00000526063; ENSP00000434104; ENSG00000133818.
DR Ensembl; ENST00000529237; ENSP00000433230; ENSG00000133818.
DR Ensembl; ENST00000532814; ENSP00000431954; ENSG00000133818.
DR Ensembl; ENST00000534746; ENSP00000437083; ENSG00000133818.
DR Ensembl; ENST00000537760; ENSP00000437547; ENSG00000133818.
DR Ensembl; ENST00000571727; ENSP00000460749; ENSG00000262489.
DR Ensembl; ENST00000572201; ENSP00000460504; ENSG00000262489.
DR Ensembl; ENST00000572397; ENSP00000459423; ENSG00000262489.
DR Ensembl; ENST00000572894; ENSP00000458232; ENSG00000262489.
DR Ensembl; ENST00000573870; ENSP00000458679; ENSG00000262489.
DR Ensembl; ENST00000574530; ENSP00000460998; ENSG00000262489.
DR GeneID; 22800; -.
DR KEGG; hsa:22800; -.
DR UCSC; uc001mlf.4; human.
DR CTD; 22800; -.
DR GeneCards; GC11M014299; -.
DR HGNC; HGNC:17271; RRAS2.
DR HPA; CAB010420; -.
DR MIM; 167000; phenotype.
DR MIM; 600098; gene.
DR neXtProt; NX_P62070; -.
DR PharmGKB; PA34862; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233973; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P62070; -.
DR KO; K07830; -.
DR OMA; XKFQEQE; -.
DR PhylomeDB; P62070; -.
DR SignaLink; P62070; -.
DR EvolutionaryTrace; P62070; -.
DR GeneWiki; RRAS2; -.
DR GenomeRNAi; 22800; -.
DR NextBio; 43146; -.
DR PRO; PR:P62070; -.
DR ArrayExpress; P62070; -.
DR Bgee; P62070; -.
DR CleanEx; HS_RRAS2; -.
DR Genevestigator; P62070; -.
DR GO; GO:0005783; C:endoplasmic reticulum; NAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; NAS:ProtInc.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; TAS:ProtInc.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; IEA:Ensembl.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR020849; Small_GTPase_Ras.
DR PANTHER; PTHR24070; PTHR24070; 1.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00173; RAS; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51421; RAS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell membrane;
KW Complete proteome; Disease mutation; GTP-binding; Lipoprotein;
KW Membrane; Methylation; Nucleotide-binding; Palmitate; Phosphoprotein;
KW Prenylation; Proto-oncogene; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 201 Ras-related protein R-Ras2.
FT /FTId=PRO_0000082652.
FT PROPEP 202 204 Removed in mature form (By similarity).
FT /FTId=PRO_0000281302.
FT NP_BIND 21 29 GTP.
FT NP_BIND 68 72 GTP (By similarity).
FT NP_BIND 127 130 GTP.
FT NP_BIND 157 159 GTP.
FT MOTIF 43 51 Effector region.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 186 186 Phosphoserine.
FT MOD_RES 201 201 Cysteine methyl ester (Probable).
FT LIPID 199 199 S-palmitoyl cysteine (Potential).
FT LIPID 201 201 S-farnesyl cysteine.
FT VAR_SEQ 1 77 Missing (in isoform 2).
FT /FTId=VSP_043066.
FT VAR_SEQ 1 36 MAAAGWRDGSGQEKYRLVVVGGGGVGKSALTIQFIQ -> M
FT (in isoform 3).
FT /FTId=VSP_044485.
FT VARIANT 72 72 Q -> L (in an ovarian cancer sample;
FT somatic mutation).
FT /FTId=VAR_006848.
FT STRAND 14 21
FT HELIX 27 36
FT STRAND 49 57
FT STRAND 60 68
FT HELIX 77 85
FT STRAND 87 94
FT HELIX 98 102
FT HELIX 104 115
FT STRAND 121 127
FT HELIX 139 148
FT STRAND 152 155
FT TURN 158 161
FT HELIX 164 178
SQ SEQUENCE 204 AA; 23400 MW; BA7D4759DC49446F CRC64;
MAAAGWRDGS GQEKYRLVVV GGGGVGKSAL TIQFIQSYFV TDYDPTIEDS YTKQCVIDDR
AARLDILDTA GQEEFGAMRE QYMRTGEGFL LVFSVTDRGS FEEIYKFQRQ ILRVKDRDEF
PMILIGNKAD LDHQRQVTQE EGQQLARQLK VTYMEASAKI RMNVDQAFHE LVRVIRKFQE
QECPPSPEPT RKEKDKKGCH CVIF
//
MIM
167000
*RECORD*
*FIELD* NO
167000
*FIELD* TI
#167000 OVARIAN CANCER
OVARIAN CANCER, EPITHELIAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because ovarian cancer has
read morebeen associated with somatic changes in several genes, including OPCML
(600632), PIK3CA (171834), AKT1 (164730), CTNNB1 (116806), RRAS2
(600098), CDH1 (192090), ERBB2 (164870), and PARK2 (602544).
See also 607893 for an ovarian cancer susceptibility locus (OVCAS1) that
has been mapped to chromosome 3p25-p22.
Familial ovarian cancer may be part of other cancer syndromes. See
susceptibility to familial breast-ovarian cancer 1 and 2 (604370 and
612555), due to mutations in the BRCA1 (113705) and BRCA2 (600185)
genes, respectively; and Lynch syndrome, also known as hereditary
nonpolyposis colorectal cancer (see, e.g., HNPCC1; 120435), due to
mutations in DNA mismatch repair genes such as MSH2 (609309), MSH3
(600887), MSH6 (600678), and MLH1 (120436).
DESCRIPTION
Ovarian cancer, the leading cause of death from gynecologic malignancy,
is characterized by advanced presentation with loco-regional
dissemination in the peritoneal cavity and the rare incidence of
visceral metastases (Chi et al., 2001). These typical features relate to
the biology of the disease, which is a principal determinant of outcome
(Auersperg et al., 2001). Epithelial ovarian cancer is the most common
form and encompasses 5 major histologic subtypes: papillary serous,
endometrioid, mucinous, clear cell, and transitional cell. Epithelial
ovarian cancer arises as a result of genetic alterations sustained by
the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008).
INHERITANCE
There are several early reports of familial ovarian cancer showing
autosomal dominant inheritance. Some of these families may have had the
breast-ovarian cancer syndrome or Lynch syndrome. Liber (1950) described
a family with histologically proven papillary adenocarcinoma of the
ovary in 5 sisters and their mother. Jackson (1967) reported a Jamaican
family in which grandmother, mother, and daughter developed ovarian
tumors; 2 tumors were known to have been dysgerminomas (see 603737).
Lewis and Davison (1969) described a family in which 5 of 6 sisters and
their mother had ovarian cancer. One of the 5 had a malignant ovarian
cyst but subsequently died of colon cancer. Prophylactic oophorectomy
was performed in the sixth sister and in 5 females of the following
generation.
Li et al. (1970) reported a family in which 7 women, including 4
sisters, had ovarian carcinoma. Ovarian cancer was suspected in 3 other
women of the family. Philip (1979) described a family with multiple
cases of poorly differentiated cystadenocarcinoma of the ovary. The 4
relatives with ovarian carcinoma were the proband's mother, maternal
aunt, that woman's daughter, and the daughter of another maternal aunt.
CYTOGENETICS
Whang-Peng et al. (1984) performed cytogenetic studies on ovarian tumor
tissue from 44 patients with various forms of epithelial ovarian cancer.
All 44 samples had numerical abnormalities, and 39 had structural
abnormalities involving multiple chromosomes. Clone formation and the
number of chromosomes involved in structural abnormalities increased
with duration of disease and were more extensive in patients treated
with chemotherapy compared to patients treated with surgery alone.
Aneuploidy was observed in all patients and there was considerable
variation in the chromosome numbers, often ranging from diploidy to
triploidy to tetraploidy.
MAPPING
- Chromosome 2q22.1
Because both ovarian and breast cancer are hormone-related and are known
to have some predisposition genes in common, Song et al. (2009)
evaluated 11 of the most significant loci from a previously reported
breast cancer genomewide association study for association with invasive
ovarian cancer (Easton et al., 2007). The 11 SNPs were initially
genotyped in 2,927 invasive ovarian cancer cases and 4,143 controls from
6 ovarian cancer case-control studies. Only dbSNP rs4954956 located less
than 7.0 kb upstream of the NXPH2 gene (604635) was significantly
associated with ovarian cancer risk both in the replication study and in
combined analysis of 5,353 patients and 8,453 controls. This association
was stronger for the serous histologic subtype (p = 0.0004; OR, 1.14)
than for all types of ovarian cancer (p = 0.05; OR, 1.07).
- Chromosome 6q25
Saito et al. (1992) examined loss of heterozygosity (LOH) in 70 ovarian
tumors using 9 RFLP markers located at chromosome 6q24-q27. Among 33
informative serous cancers, 17 (52%) showed allelic loss at a few or all
loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12
clear-cell tumors showed LOH. A detailed deletion map delineated a
1.9-cM region, within which the authors postulated the existence of a
tumor suppressor gene involved in ovarian carcinoma.
In 54 fresh and paraffin-embedded invasive ovarian epithelial tumor
tissues, Colitti et al. (1998) used tandem repeat markers on chromosome
6q25 to delineate a 4-cM minimal region of LOH of 6q25.1-q25.2 between
markers D6S473 and D6S448. Loss of heterozygosity was observed more
frequently at the loci defined by marker D6S473 (14 of 32 informative
cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). LOH at
D6S473 correlated significantly both with serous compared to non-serous
ovarian tumors (p = 0.040), and with high-grade compared to low-grade
specimens (p = 0.023).
- Chromosome 11q25
Loss of heterozygosity studies indicated that a tumor suppressor gene
associated with sporadic ovarian cancer may reside at chromosome 11q25
(Gabra et al., 1996; Launonen et al., 1998). In tumor tissue from 118
individuals with epithelial ovarian cancer, Sellar et al. (2003)
observed a peak LOH rate of 49% (36 of 74 informative cases) across
11q25 at D11S4085. Conversely, LOH analysis of 39 pairs of DNA from
individuals with colorectal cancer (see 114500) and normal DNA showed an
LOH rate at D11S4085 of only 23% (6 of 26 informative cases), with no
evidence of complete LOH.
- Chromosome 17p
Eccles et al. (1990) found LOH of chromosome 17p in 69% of 16 epithelial
ovarian cancer tumors.
Schultz et al. (1996) identified 2 genes, OVCA1 (DPH1; 603527) and OVCA2
(607896), within a minimum region of allelic loss on chromosome 17p13.3
in a cohort of ovarian tumors. Expression of OVCA1 and OVCA2 was reduced
or undetectable in ovarian tumor tissue and cell lines compared with
normal ovarian epithelial cells. The findings provided evidence for 1 or
more possible tumor suppressor genes on chromosome 17p distinct from the
TP53 gene (191170).
Phillips et al. (1996) also identified the DPH1 (OVCA1) gene within the
region on chromosome 17p13.3 that is deleted in 80% of all ovarian
epithelial malignancies. They suggested that it may act as a tumor
suppressor gene.
- Chromosome 17q
Chromosome 17q contains several genes implicated in ovarian cancer: the
BRCA1 gene (113605) on 17q21, the ERBB2 gene (164870) on 17q21.1, and
the SEPT9 gene (604061) on 17q25.
Eccles et al. (1990) found LOH of 17q in 77% of 16 epithelial ovarian
cancer tumors.
Godwin et al. (1994) examined normal and tumor DNA samples from 32
patients with sporadic and 8 patients with familial forms of epithelial
ovarian tumors. Evaluation of a set of markers positioned telomeric to
BRCA1 on chromosome 17q21 resulted in the highest degree of LOH, 73%
(29/40), indicating that a candidate locus involved in ovarian cancer
may reside distal to the BRCA1 gene.
Russell et al. (2000) isolated the SEPT9 gene, which they designated
ovarian/breast (Ov/Br) septin, as a candidate for the ovarian tumor
suppressor gene that had been indirectly identified by up to 70% LOH for
a marker at chromosome 17q25 in a bank of malignant ovarian tumors. Two
splice variants were demonstrated within the 200-kb contig, which
differed only at exon 1. The septins are a family of genes involved in
cytokinesis and cell cycle control, whose known functions are consistent
with the hypothesis that the human 17q25 septin gene may be a candidate
for the ovarian tumor suppressor gene.
Rafnar et al. (2011) performed a genomewide association study of 16
million SNPs identified through whole-genome sequencing of 457
Icelanders and imputed genotypes to 41,675 Icelanders using SNP chips,
as well as to their relatives. Sequence variants were tested for
association with ovarian cancer in 656 affected individuals. Rafnar et
al. (2011) discovered a rare (0.41% allelic frequency) frameshift
mutation, 2040_2041insTT, in the BRIP1 (also known as FANCJ; 605882)
gene that confers an increase in ovarian cancer risk (odds ratio (OR) =
8.13, p = 2.8 x 10(-14)). The mutation was also associated with
increased risk of cancer in general and reduced life span by 3.6 years.
In a Spanish population, another frameshift mutation in BRIP1,
1702_1703del, was seen in 2 of 144 subjects with ovarian cancer and 1 of
1,780 control subjects (p = 0.016). This allele was also associated with
breast cancer (seen in 6 of 927 cases; p = 0.0079). Ovarian tumors from
heterozygous carriers of the Icelandic mutation showed loss of the
wildtype allele, indicating that BRIP1 behaves like a classical tumor
suppressor gene in ovarian cancer.
- Chromosome 9p24 By transfection of NIH-3T3 cells with genomic
DNA from a human ovarian adenocarcinoma tumor cell line, Halverson et
al. (1990) identified a rearranged human DNA sequence that was generated
during transfection and induced both morphologic transformation and
tumorigenesis. One fragment mapped to human chromosome 9p24 and the
other to human chromosome 8. Because rat ovarian surface epithelial
cells transformed spontaneously in vitro have been found to have
homozygous deletions of the interferon alpha gene (IFNA; 147660) on
9p22, suggesting inactivation of a tumor-suppressor gene in that region
may be crucial for the development of ovarian cancer, Chenevix-Trench et
al. (1994) used microsatellite markers and Southern analysis to examine
the homologous region in humans, 9p, for deletions in sporadic ovarian
adenocarcinomas and ovarian tumor cell lines. Loss of heterozygosity
occurred in 34 (37%) of 91 informative sporadic tumors, including some
benign, low-malignant-potential and early-stage tumors, suggesting that
it is an early event in the development of ovarian adenocarcinoma.
Furthermore, homozygous deletions on 9p were found in 2 of 10
independent cell lines. Deletion mapping of the tumors and cell lines
indicated that the candidate suppressor gene inactivated as a
consequence lies between D9S171 and the IFNA locus. This region is
deleted in several other tumors and contains a melanoma predisposition
locus (155601). In a note added in proof, Chenevix-Trench et al. (1994)
suggested that the target of these 9p deletions might be CDKN2 (600160)
as described by Kamb et al. (1994).
MOLECULAR GENETICS
- Germline Mutations
Stratton et al. (1999) conducted a population-based study to determine
the contribution of germline mutations in known candidate genes to
epithelial ovarian cancer diagnosed before the age of 30 years. Two of
101 women with invasive ovarian cancer had germline mutations in the
MLH1 gene (120436), which is involved in hereditary nonpolyposis
colorectal cancer-2 (HNPCC2; 609310). In addition to colon cancer,
ovarian cancer may be a manifestation of this syndrome. No germline
mutations were identified in any of the other genes analyzed, including
BRCA1, the 'ovarian cancer-cluster region' (nucleotides 3139-7069) of
BRCA2, and MSH2. There were no striking pedigrees suggestive of families
with either breast/ovarian cancer or HNPCC. There was a significantly
increased incidence of all cancers in first-degree relatives of women
with invasive disease (relative risk = 1.6, P = 0.01), but not in
second-degree relatives or in relatives of women with borderline cases.
First-degree relatives of women with invasive disease had an increased
risk of ovarian cancer, myeloma, and non-Hodgkin lymphoma. The data
indicated that germline mutations in BRCA1, BRCA2, MSH2, and MLH1
contribute to only a minority of cases of early-onset epithelial ovarian
cancer.
Liede et al. (1998) raised the question of the existence of hereditary
site-specific ovarian cancer as a genetic entity distinct from
hereditary breast-ovarian cancer syndrome. They identified a large
Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases
of breast cancer. However, in all but 1 of the ovarian cancer cases, the
185delAG mutation in the BRCA1 gene (113705.0003) segregated with the
cancer. Liede et al. (1998) concluded that site-specific ovarian cancer
families probably represent a variant of the breast-ovarian cancer
syndrome, attributable to mutation in either BRCA1 or BRCA2.
- Somatic Mutations
Cesari et al. (2003) identified the complete PARK2 gene (602544) within
an LOH region on chromosome 6q25-q27. LOH analysis of 40 malignant
breast and ovarian tumors identified a common minimal region of loss,
including the markers D6S305 (50%) and D6S1599 (32%), both of which are
located within the PARK2 gene. Expression of the PARK2 gene appeared to
be downregulated or absent in the tumor biopsies and tumor cell lines
examined. In addition, Cesari et al. (2003) found 2 somatic truncating
deletions in the PARK2 gene (see, e.g., 602544.0016) in 3 of 20 ovarian
cancers. The data suggested that PARK2 may act as a tumor suppressor
gene. Because PARK2 maps to FRA6E, one of the most active common fragile
sites in the human genome (Smith et al., 1998), it may represent another
example of a large tumor suppressor gene, like FHIT (601153) and WWOX
(605131), located at a common fragile site. Denison et al. (2003) found
that 4 (66.7%) ovarian cancer cell lines and 4 (18.2%) primary ovarian
tumors were heterozygous for the duplication or deletion of 1 or more
exons in the PARK2 gene. Additionally, 3 of 23 (13%) nonovarian
tumor-derived cell lines were found to have a duplication or deletion of
1 or more parkin exons. Diminished or absent parkin expression was
observed in most of the ovarian cancer cell lines when studies with
antibodies were performed. Denison et al. (2003) suggested that parkin
may represent a tumor suppressor gene.
Sellar et al. (2003) determined that D11S4085 on 11q25 is located in the
second intron of the OPCML gene (600632). OPCML was frequently
somatically inactivated in epithelial ovarian cancer tissue by allele
loss and by CpG island methylation. OPCML has functional characteristics
consistent with tumor suppressor gene properties both in vitro and in
vivo. A somatic missense mutation from an individual with epithelial
ovarian cancer showed clear evidence of loss of function (600632.0001).
These findings suggested that OPCML was an excellent candidate for an
ovarian cancer tumor suppressor gene located on 11q25.
By examining DNA copy number of 283 known miRNA genes, Zhang et al.
(2006) found a high proportion of copy number abnormalities in 227 human
ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA
copy number correlated with miRNA expression. They also found a high
frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2;
606229), and other miRNA-associated genes in these cancers. Zhang et al.
(2006) concluded that copy number alterations of miRNAs and their
regulatory genes are highly prevalent in cancer and may account partly
for the frequent miRNA gene deregulation reported in several tumor
types.
Kan et al. (2010) reported the identification of 2,576 somatic mutations
across approximately 1,800 megabases of DNA representing 1,507 coding
genes from 441 tumors comprising breast, lung, ovarian, and prostate
cancer types and subtypes. Kan et al. (2010) found that mutation rates
and the sets of mutated genes varied substantially across tumor types
and subtypes. Statistical analysis identified 77 significantly mutated
genes including protein kinases, G protein-coupled receptors such as
GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other
druggable targets. Integrated analysis of somatic mutations and copy
number alterations identified another 35 significantly altered genes
including GNAS (see 139320), indicating an expanded role for G-alpha
subunits in multiple cancer types. Experimental analyses demonstrated
the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335)
in oncogenesis.
The Cancer Genome Atlas Research Network (2011) reported that high-grade
serous ovarian cancer is characterized by TP53 (191170) mutations in
almost all tumors (96% of 489 high-grade serous ovarian
adenocarcinomas); low prevalence but statistically recurrent somatic
mutations in 9 further genes including NF1 (613113), BRCA1 (113705),
BRCA2 (600185), RB1 (614041), and CDK12 (615514); 113 significant focal
DNA copy number aberrations; and promoter methylation events involving
168 genes. Analyses delineated 4 ovarian cancer transcriptional
subtypes, 3 microRNA subtypes, 4 promoter methylation subtypes, and a
transcriptional signature associated with survival duration, and shed
new light on the impact that tumors with BRCA1/2 and CCNE1 (123837)
aberrations have on survival. Pathway analyses suggested that homologous
recombination is defective in about half of the tumors analyzed, and
that NOTCH (190198) and FOXM1 (602341) signaling are involved in serous
ovarian cancer pathophysiology.
- Modifier Genes
Quaye et al. (2009) used microcell-mediated chromosome transfer approach
and expression microarray analysis to identify candidate genes that were
associated with neoplastic suppression in ovarian cancer cell lines. In
over 1,600 ovarian cancer patients from 3 European population-based
studies, they genotyped 68 tagging SNPs from 9 candidate genes and found
a significant association between survival and 2 tagging SNPs in the
RBBP8 gene (604124), dbSNP rs4474794 (hazard ratio, 0.85; 95% CI,
0.75-0.95; p = 0.007) and dbSNP rs9304261 (hazard ratio, 0.83; 95% CI,
0.71-0.95; p = 0.009). Loss of heterozygosity (LOH) analysis of tagging
SNPs in 314 ovarian tumors identified associations between somatic gene
deletions and survival. Thirty-five percent of tumors in 101 informative
cases showed LOH for the RBBP8 gene, which was associated with a
significantly worse prognosis (hazard ratio, 2.19; 95% CI, 1.36-3.54; p
= 0.001). Quaye et al. (2009) concluded that germline genetic variation
and somatic alterations of the RBBP8 gene in tumors are associated with
survival in ovarian cancer patients.
CLINICAL MANAGEMENT
Chien et al. (2006) studied HTRA1 (PRSS11; 602194) expression in tumors
from 60 patients with epithelial ovarian cancer and 51 with gastric
cancer (137215) and found that those with tumors expressing higher
levels of HTRA1 showed a significantly higher response rate to
chemotherapy than those with lower levels of HTRA1 expression. Chien et
al. (2006) suggested that loss of HTRA1 in ovarian and gastric cancers
may contribute to in vivo chemoresistance.
PATHOGENESIS
Using a PCR-based differential display method, Mok et al. (1994)
identified a gene, termed DOC2 (601236), that was expressed in normal
ovarian epithelial cells, but downregulated or absent from ovarian
carcinoma cell lines. The DOC2 gene maps to chromosome 5p13. Mok et al.
(1998) reported that transfection of the DOC2 gene into an ovarian
carcinoma cell line resulted in significantly reduced growth rate and
ability to form tumors in nude mice.
Among 48 primary ovarian cancer tumors and corresponding metastases,
Blechschmidt et al. (2008) found a significant association (p = 0.008)
between reduced E-cadherin (CDH1) expression in the primary cancer
tissue and shorter overall survival. Patients with decreased E-cadherin
expression and increased SNAIL (SNAI1; 604238) expression in the primary
tumor showed a higher risk of death (p = 0.002). There was no
significant difference in expression of E-cadherin or SNAIL between
primary tumors and metastases. The findings were consistent with a role
for E-cadherin and SNAIL in the behavior of metastatic cancer.
Merritt et al. (2008) observed decreased mRNA and protein expression of
the RNAse III enzymes DICER1 (606241) and DROSHA (RNASEN; 608828) in 60
and 51%, respectively, of 111 invasive epithelial ovarian cancer
specimens. Low DICER1 expression was significantly associated with
advanced tumor stage (p = 0.007), and low DROSHA expression with
suboptimal surgical cytoreduction (p = 0.02). Cancer specimens with both
high DICER1 expression and high DROSHA expression were associated with
increased median survival (greater than 11 years vs 2.66 years for other
subgroups; p less than 0.001). Statistical analysis revealed 3
independent predictors of reduced disease-specific survival: low DICER1
expression (hazard ratio, 2.10; p = 0.02), high-grade histologic
features (hazard ratio, 2.46; p = 0.03), and poor response to
chemotherapy (hazard ratio, 3.95; p less than 0.001). Poor clinical
outcomes among patients with low DICER1 expression were validated in an
additional cohort of patients. Although rare missense variants were
found in both genes, the presence or absence did not correlate with the
level of expression. Functional assays indicated that gene silencing
with shRNA, but not siRNA, may be impaired in cells with low DICER1
expression. The findings implicated a component of the RNA-interference
machinery, which regulates gene expression, in the pathogenesis of
ovarian cancer. Merritt et al. (2009) noted that 109 of the 111 samples
used in the 2008 study had serous histologic features, of which 93 were
high-grade and 16 low-grade tumors.
To explore the genetic origin of ovarian clear cell carcinoma, Jones et
al. (2010) determined the exomic sequences of 8 tumors after
immunoaffinity purification of cancer cells. Through comparative
analyses of normal cells from the same patients, Jones et al. (2010)
identified 4 genes that were mutated in at least 2 tumors. PIK3CA
(171834), which encodes a subunit of phosphatidylinositol-3 kinase, and
KRAS (190070), which encodes a well-known oncoprotein, had previously
been implicated in ovarian clear cell carcinoma. The other 2 mutated
genes were previously unknown to be involved in ovarian clear cell
carcinoma: PPP2R1A (605983) encodes a regulatory subunit of
serine/threonine phosphatase-2, and ARID1A (603024) encodes
adenine-thymine (AT)-rich interactive domain-containing protein 1A,
which participates in chromatin remodeling. The nature and pattern of
the mutations suggested that PPP2R1A functions as an oncogene and ARID1A
as a tumor suppressor gene. In a total of 42 ovarian clear cell
carcinomas, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A.
Jones et al. (2010) concluded that their results suggested that aberrant
chromatin remodeling contributes to the pathogenesis of ovarian clear
cell carcinoma.
Flesken-Nikitin et al. (2013) identified the hilum region of the mouse
ovary, the transitional (or junction) area between the ovarian surface
epithelium, mesothelium, and tubal (oviductal) epithelium, as a stem
cell niche of the ovarian surface epithelium (OSE). They found that
cells of the hilum OSE are cycling slowly and express stem and/or
progenitor cell markers ALDH1 (100640), LGR5 (606667), LEF1 (153245),
CD133 (604365), and CK6B (148042). These cells display long-term stem
cell properties ex vivo and in vivo, as shown by serial sphere
generation and long-term lineage-tracing assays. Importantly, the hilum
cells showed increased transformation potential after inactivation of
tumor suppressor genes Trp53 (191170) and Rb1 (614041), whose pathways
are altered frequently in the most aggressive and common type of human
epithelial ovarian cancer, high-grade serous adenocarcinoma.
Flesken-Nikitin et al. (2013) concluded that their study supported
experimentally the idea that susceptibility of transitional zones to
malignant transformation may be explained by the presence of stem cell
niches in these areas.
GENOTYPE/PHENOTYPE CORRELATIONS
Grindedal et al. (2010) performed a retrospective survival study of 144
women with ovarian cancer due to MMR mutations. Fifty-one (35.4%) had a
mutation in MLH1, 78 (54.2%) had a mutation in MSH2, and 15 (10.4%) had
a mutation in MSH6. The mean age of onset was 44.7 years, compared to
51.2 years in carriers of BRCA1 (113705) mutations with ovarian cancer
and 57.5 in carriers of BRCA2 (600185) mutations with ovarian cancer
(Risch et al., 2001). Most (81.5%) women with MMR mutations were
diagnosed at stage 1 or 2. Twenty-nine (20.1%) of 144 woman with
MMR-related ovarian cancer died of their ovarian cancer. The 5-, 10-,
20- and 30-year survival specific for deaths due to ovarian cancers were
82.7%, 80.6%, 78.0% and 71.5%, respectively. About 50% of the women
developed another cancer in the HNPCC/Lynch syndrome tumor spectrum. The
5-, 10-, 20-, and 30-year survival specific for deaths due to
HNPCC/Lynch syndrome-associated cancers were 79.2%, 75.7%, 68.4% and
47.3%, respectively. Overall, the survival for women with ovarian cancer
due to MMR mutations was better than for those with ovarian cancer due
to BRCA1/2 mutations, which is less than 40% at 10 years. The lifetime
risk of ovarian cancer in MMR mutation carriers was about 10% and the
risk of dying from ovarian cancer was 20%, yielding an overall risk of
dying from ovarian cancer of about 2% in MMR mutation carriers.
Grindedal et al. (2010) suggested that mutations in the MMR and BRCA1/2
genes may predispose to biologically different types of tumors.
ANIMAL MODEL
Dinulescu et al. (2005) developed a mouse model of ovarian cancer. A
recombinant adenoviral vector expressing an oncogenic Kras (190070)
allele within the ovarian surface epithelium resulted in the development
of benign epithelial lesions with a typical endometrioid glandular
morphology that did not progress to ovarian carcinoma; 7 of 15 mice
(47%) also developed peritoneal endometriosis (131200). When the Kras
mutation was combined with conditional deletion of Pten (601728), all
mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu
et al. (2005) stated that these were the first mouse models of
endometriosis and endometrioid adenocarcinoma of the ovary.
*FIELD* SA
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A.; Liang, S.; Naylor, T. L.; Barchetti, A.; Ward, M. R.; Yao, G.;
Medina, A.; O'Brien-Jenkins, A.; Katsaros, D.; Hatzigeorgiou, A.;
Gimotty, P. A.; Weber, B. L.; Coukos, G.: MicroRNAs exhibit high
frequency genomic alterations in human cancer. Proc. Nat. Acad. Sci. 103:
9136-9141, 2006.
*FIELD* CS
Oncology:
Ovarian cancer;
Dysgerminoma;
Ovarian papillary adenocarcinoma;
Serous ovarian cystadenocarcinoma;
Breast cancer
Lab:
Frequent loss of heterozygosity at 6q24-q27
Inheritance:
Autosomal dominant
*FIELD* CN
Ada Hamosh - updated: 4/1/2013
Ada Hamosh - updated: 7/26/2012
Ada Hamosh - updated: 7/23/2012
Ada Hamosh - updated: 8/24/2011
Ada Hamosh - updated: 11/4/2010
Ada Hamosh - updated: 9/21/2010
Cassandra L. Kniffin - updated: 6/4/2010
George E. Tiller - updated: 3/2/2010
George E. Tiller - updated: 2/22/2010
Cassandra L. Kniffin - updated: 3/19/2009
Cassandra L. Kniffin - reorganized: 2/6/2009
Cassandra L. Kniffin - updated: 1/30/2009
Victor A. McKusick - updated: 3/13/1998
Victor A. McKusick - updated: 2/24/1998
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
mgross: 11/20/2013
carol: 10/1/2013
terry: 4/4/2013
alopez: 4/3/2013
terry: 4/1/2013
alopez: 10/3/2012
terry: 8/8/2012
alopez: 7/26/2012
terry: 7/23/2012
alopez: 8/26/2011
terry: 8/24/2011
alopez: 11/11/2010
terry: 11/4/2010
alopez: 9/23/2010
terry: 9/21/2010
wwang: 6/9/2010
ckniffin: 6/4/2010
wwang: 3/15/2010
terry: 3/2/2010
wwang: 2/24/2010
terry: 2/22/2010
terry: 6/3/2009
wwang: 3/20/2009
ckniffin: 3/19/2009
carol: 2/6/2009
terry: 2/6/2009
terry: 2/2/2009
ckniffin: 1/30/2009
carol: 3/17/2004
carol: 8/19/1999
carol: 5/12/1998
alopez: 3/13/1998
terry: 3/10/1998
dholmes: 2/24/1998
dholmes: 2/18/1998
mark: 7/30/1995
mimadm: 1/14/1995
carol: 9/8/1993
carol: 7/1/1992
supermim: 3/16/1992
carol: 3/8/1992
*RECORD*
*FIELD* NO
167000
*FIELD* TI
#167000 OVARIAN CANCER
OVARIAN CANCER, EPITHELIAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because ovarian cancer has
read morebeen associated with somatic changes in several genes, including OPCML
(600632), PIK3CA (171834), AKT1 (164730), CTNNB1 (116806), RRAS2
(600098), CDH1 (192090), ERBB2 (164870), and PARK2 (602544).
See also 607893 for an ovarian cancer susceptibility locus (OVCAS1) that
has been mapped to chromosome 3p25-p22.
Familial ovarian cancer may be part of other cancer syndromes. See
susceptibility to familial breast-ovarian cancer 1 and 2 (604370 and
612555), due to mutations in the BRCA1 (113705) and BRCA2 (600185)
genes, respectively; and Lynch syndrome, also known as hereditary
nonpolyposis colorectal cancer (see, e.g., HNPCC1; 120435), due to
mutations in DNA mismatch repair genes such as MSH2 (609309), MSH3
(600887), MSH6 (600678), and MLH1 (120436).
DESCRIPTION
Ovarian cancer, the leading cause of death from gynecologic malignancy,
is characterized by advanced presentation with loco-regional
dissemination in the peritoneal cavity and the rare incidence of
visceral metastases (Chi et al., 2001). These typical features relate to
the biology of the disease, which is a principal determinant of outcome
(Auersperg et al., 2001). Epithelial ovarian cancer is the most common
form and encompasses 5 major histologic subtypes: papillary serous,
endometrioid, mucinous, clear cell, and transitional cell. Epithelial
ovarian cancer arises as a result of genetic alterations sustained by
the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008).
INHERITANCE
There are several early reports of familial ovarian cancer showing
autosomal dominant inheritance. Some of these families may have had the
breast-ovarian cancer syndrome or Lynch syndrome. Liber (1950) described
a family with histologically proven papillary adenocarcinoma of the
ovary in 5 sisters and their mother. Jackson (1967) reported a Jamaican
family in which grandmother, mother, and daughter developed ovarian
tumors; 2 tumors were known to have been dysgerminomas (see 603737).
Lewis and Davison (1969) described a family in which 5 of 6 sisters and
their mother had ovarian cancer. One of the 5 had a malignant ovarian
cyst but subsequently died of colon cancer. Prophylactic oophorectomy
was performed in the sixth sister and in 5 females of the following
generation.
Li et al. (1970) reported a family in which 7 women, including 4
sisters, had ovarian carcinoma. Ovarian cancer was suspected in 3 other
women of the family. Philip (1979) described a family with multiple
cases of poorly differentiated cystadenocarcinoma of the ovary. The 4
relatives with ovarian carcinoma were the proband's mother, maternal
aunt, that woman's daughter, and the daughter of another maternal aunt.
CYTOGENETICS
Whang-Peng et al. (1984) performed cytogenetic studies on ovarian tumor
tissue from 44 patients with various forms of epithelial ovarian cancer.
All 44 samples had numerical abnormalities, and 39 had structural
abnormalities involving multiple chromosomes. Clone formation and the
number of chromosomes involved in structural abnormalities increased
with duration of disease and were more extensive in patients treated
with chemotherapy compared to patients treated with surgery alone.
Aneuploidy was observed in all patients and there was considerable
variation in the chromosome numbers, often ranging from diploidy to
triploidy to tetraploidy.
MAPPING
- Chromosome 2q22.1
Because both ovarian and breast cancer are hormone-related and are known
to have some predisposition genes in common, Song et al. (2009)
evaluated 11 of the most significant loci from a previously reported
breast cancer genomewide association study for association with invasive
ovarian cancer (Easton et al., 2007). The 11 SNPs were initially
genotyped in 2,927 invasive ovarian cancer cases and 4,143 controls from
6 ovarian cancer case-control studies. Only dbSNP rs4954956 located less
than 7.0 kb upstream of the NXPH2 gene (604635) was significantly
associated with ovarian cancer risk both in the replication study and in
combined analysis of 5,353 patients and 8,453 controls. This association
was stronger for the serous histologic subtype (p = 0.0004; OR, 1.14)
than for all types of ovarian cancer (p = 0.05; OR, 1.07).
- Chromosome 6q25
Saito et al. (1992) examined loss of heterozygosity (LOH) in 70 ovarian
tumors using 9 RFLP markers located at chromosome 6q24-q27. Among 33
informative serous cancers, 17 (52%) showed allelic loss at a few or all
loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12
clear-cell tumors showed LOH. A detailed deletion map delineated a
1.9-cM region, within which the authors postulated the existence of a
tumor suppressor gene involved in ovarian carcinoma.
In 54 fresh and paraffin-embedded invasive ovarian epithelial tumor
tissues, Colitti et al. (1998) used tandem repeat markers on chromosome
6q25 to delineate a 4-cM minimal region of LOH of 6q25.1-q25.2 between
markers D6S473 and D6S448. Loss of heterozygosity was observed more
frequently at the loci defined by marker D6S473 (14 of 32 informative
cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). LOH at
D6S473 correlated significantly both with serous compared to non-serous
ovarian tumors (p = 0.040), and with high-grade compared to low-grade
specimens (p = 0.023).
- Chromosome 11q25
Loss of heterozygosity studies indicated that a tumor suppressor gene
associated with sporadic ovarian cancer may reside at chromosome 11q25
(Gabra et al., 1996; Launonen et al., 1998). In tumor tissue from 118
individuals with epithelial ovarian cancer, Sellar et al. (2003)
observed a peak LOH rate of 49% (36 of 74 informative cases) across
11q25 at D11S4085. Conversely, LOH analysis of 39 pairs of DNA from
individuals with colorectal cancer (see 114500) and normal DNA showed an
LOH rate at D11S4085 of only 23% (6 of 26 informative cases), with no
evidence of complete LOH.
- Chromosome 17p
Eccles et al. (1990) found LOH of chromosome 17p in 69% of 16 epithelial
ovarian cancer tumors.
Schultz et al. (1996) identified 2 genes, OVCA1 (DPH1; 603527) and OVCA2
(607896), within a minimum region of allelic loss on chromosome 17p13.3
in a cohort of ovarian tumors. Expression of OVCA1 and OVCA2 was reduced
or undetectable in ovarian tumor tissue and cell lines compared with
normal ovarian epithelial cells. The findings provided evidence for 1 or
more possible tumor suppressor genes on chromosome 17p distinct from the
TP53 gene (191170).
Phillips et al. (1996) also identified the DPH1 (OVCA1) gene within the
region on chromosome 17p13.3 that is deleted in 80% of all ovarian
epithelial malignancies. They suggested that it may act as a tumor
suppressor gene.
- Chromosome 17q
Chromosome 17q contains several genes implicated in ovarian cancer: the
BRCA1 gene (113605) on 17q21, the ERBB2 gene (164870) on 17q21.1, and
the SEPT9 gene (604061) on 17q25.
Eccles et al. (1990) found LOH of 17q in 77% of 16 epithelial ovarian
cancer tumors.
Godwin et al. (1994) examined normal and tumor DNA samples from 32
patients with sporadic and 8 patients with familial forms of epithelial
ovarian tumors. Evaluation of a set of markers positioned telomeric to
BRCA1 on chromosome 17q21 resulted in the highest degree of LOH, 73%
(29/40), indicating that a candidate locus involved in ovarian cancer
may reside distal to the BRCA1 gene.
Russell et al. (2000) isolated the SEPT9 gene, which they designated
ovarian/breast (Ov/Br) septin, as a candidate for the ovarian tumor
suppressor gene that had been indirectly identified by up to 70% LOH for
a marker at chromosome 17q25 in a bank of malignant ovarian tumors. Two
splice variants were demonstrated within the 200-kb contig, which
differed only at exon 1. The septins are a family of genes involved in
cytokinesis and cell cycle control, whose known functions are consistent
with the hypothesis that the human 17q25 septin gene may be a candidate
for the ovarian tumor suppressor gene.
Rafnar et al. (2011) performed a genomewide association study of 16
million SNPs identified through whole-genome sequencing of 457
Icelanders and imputed genotypes to 41,675 Icelanders using SNP chips,
as well as to their relatives. Sequence variants were tested for
association with ovarian cancer in 656 affected individuals. Rafnar et
al. (2011) discovered a rare (0.41% allelic frequency) frameshift
mutation, 2040_2041insTT, in the BRIP1 (also known as FANCJ; 605882)
gene that confers an increase in ovarian cancer risk (odds ratio (OR) =
8.13, p = 2.8 x 10(-14)). The mutation was also associated with
increased risk of cancer in general and reduced life span by 3.6 years.
In a Spanish population, another frameshift mutation in BRIP1,
1702_1703del, was seen in 2 of 144 subjects with ovarian cancer and 1 of
1,780 control subjects (p = 0.016). This allele was also associated with
breast cancer (seen in 6 of 927 cases; p = 0.0079). Ovarian tumors from
heterozygous carriers of the Icelandic mutation showed loss of the
wildtype allele, indicating that BRIP1 behaves like a classical tumor
suppressor gene in ovarian cancer.
- Chromosome 9p24 By transfection of NIH-3T3 cells with genomic
DNA from a human ovarian adenocarcinoma tumor cell line, Halverson et
al. (1990) identified a rearranged human DNA sequence that was generated
during transfection and induced both morphologic transformation and
tumorigenesis. One fragment mapped to human chromosome 9p24 and the
other to human chromosome 8. Because rat ovarian surface epithelial
cells transformed spontaneously in vitro have been found to have
homozygous deletions of the interferon alpha gene (IFNA; 147660) on
9p22, suggesting inactivation of a tumor-suppressor gene in that region
may be crucial for the development of ovarian cancer, Chenevix-Trench et
al. (1994) used microsatellite markers and Southern analysis to examine
the homologous region in humans, 9p, for deletions in sporadic ovarian
adenocarcinomas and ovarian tumor cell lines. Loss of heterozygosity
occurred in 34 (37%) of 91 informative sporadic tumors, including some
benign, low-malignant-potential and early-stage tumors, suggesting that
it is an early event in the development of ovarian adenocarcinoma.
Furthermore, homozygous deletions on 9p were found in 2 of 10
independent cell lines. Deletion mapping of the tumors and cell lines
indicated that the candidate suppressor gene inactivated as a
consequence lies between D9S171 and the IFNA locus. This region is
deleted in several other tumors and contains a melanoma predisposition
locus (155601). In a note added in proof, Chenevix-Trench et al. (1994)
suggested that the target of these 9p deletions might be CDKN2 (600160)
as described by Kamb et al. (1994).
MOLECULAR GENETICS
- Germline Mutations
Stratton et al. (1999) conducted a population-based study to determine
the contribution of germline mutations in known candidate genes to
epithelial ovarian cancer diagnosed before the age of 30 years. Two of
101 women with invasive ovarian cancer had germline mutations in the
MLH1 gene (120436), which is involved in hereditary nonpolyposis
colorectal cancer-2 (HNPCC2; 609310). In addition to colon cancer,
ovarian cancer may be a manifestation of this syndrome. No germline
mutations were identified in any of the other genes analyzed, including
BRCA1, the 'ovarian cancer-cluster region' (nucleotides 3139-7069) of
BRCA2, and MSH2. There were no striking pedigrees suggestive of families
with either breast/ovarian cancer or HNPCC. There was a significantly
increased incidence of all cancers in first-degree relatives of women
with invasive disease (relative risk = 1.6, P = 0.01), but not in
second-degree relatives or in relatives of women with borderline cases.
First-degree relatives of women with invasive disease had an increased
risk of ovarian cancer, myeloma, and non-Hodgkin lymphoma. The data
indicated that germline mutations in BRCA1, BRCA2, MSH2, and MLH1
contribute to only a minority of cases of early-onset epithelial ovarian
cancer.
Liede et al. (1998) raised the question of the existence of hereditary
site-specific ovarian cancer as a genetic entity distinct from
hereditary breast-ovarian cancer syndrome. They identified a large
Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases
of breast cancer. However, in all but 1 of the ovarian cancer cases, the
185delAG mutation in the BRCA1 gene (113705.0003) segregated with the
cancer. Liede et al. (1998) concluded that site-specific ovarian cancer
families probably represent a variant of the breast-ovarian cancer
syndrome, attributable to mutation in either BRCA1 or BRCA2.
- Somatic Mutations
Cesari et al. (2003) identified the complete PARK2 gene (602544) within
an LOH region on chromosome 6q25-q27. LOH analysis of 40 malignant
breast and ovarian tumors identified a common minimal region of loss,
including the markers D6S305 (50%) and D6S1599 (32%), both of which are
located within the PARK2 gene. Expression of the PARK2 gene appeared to
be downregulated or absent in the tumor biopsies and tumor cell lines
examined. In addition, Cesari et al. (2003) found 2 somatic truncating
deletions in the PARK2 gene (see, e.g., 602544.0016) in 3 of 20 ovarian
cancers. The data suggested that PARK2 may act as a tumor suppressor
gene. Because PARK2 maps to FRA6E, one of the most active common fragile
sites in the human genome (Smith et al., 1998), it may represent another
example of a large tumor suppressor gene, like FHIT (601153) and WWOX
(605131), located at a common fragile site. Denison et al. (2003) found
that 4 (66.7%) ovarian cancer cell lines and 4 (18.2%) primary ovarian
tumors were heterozygous for the duplication or deletion of 1 or more
exons in the PARK2 gene. Additionally, 3 of 23 (13%) nonovarian
tumor-derived cell lines were found to have a duplication or deletion of
1 or more parkin exons. Diminished or absent parkin expression was
observed in most of the ovarian cancer cell lines when studies with
antibodies were performed. Denison et al. (2003) suggested that parkin
may represent a tumor suppressor gene.
Sellar et al. (2003) determined that D11S4085 on 11q25 is located in the
second intron of the OPCML gene (600632). OPCML was frequently
somatically inactivated in epithelial ovarian cancer tissue by allele
loss and by CpG island methylation. OPCML has functional characteristics
consistent with tumor suppressor gene properties both in vitro and in
vivo. A somatic missense mutation from an individual with epithelial
ovarian cancer showed clear evidence of loss of function (600632.0001).
These findings suggested that OPCML was an excellent candidate for an
ovarian cancer tumor suppressor gene located on 11q25.
By examining DNA copy number of 283 known miRNA genes, Zhang et al.
(2006) found a high proportion of copy number abnormalities in 227 human
ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA
copy number correlated with miRNA expression. They also found a high
frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2;
606229), and other miRNA-associated genes in these cancers. Zhang et al.
(2006) concluded that copy number alterations of miRNAs and their
regulatory genes are highly prevalent in cancer and may account partly
for the frequent miRNA gene deregulation reported in several tumor
types.
Kan et al. (2010) reported the identification of 2,576 somatic mutations
across approximately 1,800 megabases of DNA representing 1,507 coding
genes from 441 tumors comprising breast, lung, ovarian, and prostate
cancer types and subtypes. Kan et al. (2010) found that mutation rates
and the sets of mutated genes varied substantially across tumor types
and subtypes. Statistical analysis identified 77 significantly mutated
genes including protein kinases, G protein-coupled receptors such as
GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other
druggable targets. Integrated analysis of somatic mutations and copy
number alterations identified another 35 significantly altered genes
including GNAS (see 139320), indicating an expanded role for G-alpha
subunits in multiple cancer types. Experimental analyses demonstrated
the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335)
in oncogenesis.
The Cancer Genome Atlas Research Network (2011) reported that high-grade
serous ovarian cancer is characterized by TP53 (191170) mutations in
almost all tumors (96% of 489 high-grade serous ovarian
adenocarcinomas); low prevalence but statistically recurrent somatic
mutations in 9 further genes including NF1 (613113), BRCA1 (113705),
BRCA2 (600185), RB1 (614041), and CDK12 (615514); 113 significant focal
DNA copy number aberrations; and promoter methylation events involving
168 genes. Analyses delineated 4 ovarian cancer transcriptional
subtypes, 3 microRNA subtypes, 4 promoter methylation subtypes, and a
transcriptional signature associated with survival duration, and shed
new light on the impact that tumors with BRCA1/2 and CCNE1 (123837)
aberrations have on survival. Pathway analyses suggested that homologous
recombination is defective in about half of the tumors analyzed, and
that NOTCH (190198) and FOXM1 (602341) signaling are involved in serous
ovarian cancer pathophysiology.
- Modifier Genes
Quaye et al. (2009) used microcell-mediated chromosome transfer approach
and expression microarray analysis to identify candidate genes that were
associated with neoplastic suppression in ovarian cancer cell lines. In
over 1,600 ovarian cancer patients from 3 European population-based
studies, they genotyped 68 tagging SNPs from 9 candidate genes and found
a significant association between survival and 2 tagging SNPs in the
RBBP8 gene (604124), dbSNP rs4474794 (hazard ratio, 0.85; 95% CI,
0.75-0.95; p = 0.007) and dbSNP rs9304261 (hazard ratio, 0.83; 95% CI,
0.71-0.95; p = 0.009). Loss of heterozygosity (LOH) analysis of tagging
SNPs in 314 ovarian tumors identified associations between somatic gene
deletions and survival. Thirty-five percent of tumors in 101 informative
cases showed LOH for the RBBP8 gene, which was associated with a
significantly worse prognosis (hazard ratio, 2.19; 95% CI, 1.36-3.54; p
= 0.001). Quaye et al. (2009) concluded that germline genetic variation
and somatic alterations of the RBBP8 gene in tumors are associated with
survival in ovarian cancer patients.
CLINICAL MANAGEMENT
Chien et al. (2006) studied HTRA1 (PRSS11; 602194) expression in tumors
from 60 patients with epithelial ovarian cancer and 51 with gastric
cancer (137215) and found that those with tumors expressing higher
levels of HTRA1 showed a significantly higher response rate to
chemotherapy than those with lower levels of HTRA1 expression. Chien et
al. (2006) suggested that loss of HTRA1 in ovarian and gastric cancers
may contribute to in vivo chemoresistance.
PATHOGENESIS
Using a PCR-based differential display method, Mok et al. (1994)
identified a gene, termed DOC2 (601236), that was expressed in normal
ovarian epithelial cells, but downregulated or absent from ovarian
carcinoma cell lines. The DOC2 gene maps to chromosome 5p13. Mok et al.
(1998) reported that transfection of the DOC2 gene into an ovarian
carcinoma cell line resulted in significantly reduced growth rate and
ability to form tumors in nude mice.
Among 48 primary ovarian cancer tumors and corresponding metastases,
Blechschmidt et al. (2008) found a significant association (p = 0.008)
between reduced E-cadherin (CDH1) expression in the primary cancer
tissue and shorter overall survival. Patients with decreased E-cadherin
expression and increased SNAIL (SNAI1; 604238) expression in the primary
tumor showed a higher risk of death (p = 0.002). There was no
significant difference in expression of E-cadherin or SNAIL between
primary tumors and metastases. The findings were consistent with a role
for E-cadherin and SNAIL in the behavior of metastatic cancer.
Merritt et al. (2008) observed decreased mRNA and protein expression of
the RNAse III enzymes DICER1 (606241) and DROSHA (RNASEN; 608828) in 60
and 51%, respectively, of 111 invasive epithelial ovarian cancer
specimens. Low DICER1 expression was significantly associated with
advanced tumor stage (p = 0.007), and low DROSHA expression with
suboptimal surgical cytoreduction (p = 0.02). Cancer specimens with both
high DICER1 expression and high DROSHA expression were associated with
increased median survival (greater than 11 years vs 2.66 years for other
subgroups; p less than 0.001). Statistical analysis revealed 3
independent predictors of reduced disease-specific survival: low DICER1
expression (hazard ratio, 2.10; p = 0.02), high-grade histologic
features (hazard ratio, 2.46; p = 0.03), and poor response to
chemotherapy (hazard ratio, 3.95; p less than 0.001). Poor clinical
outcomes among patients with low DICER1 expression were validated in an
additional cohort of patients. Although rare missense variants were
found in both genes, the presence or absence did not correlate with the
level of expression. Functional assays indicated that gene silencing
with shRNA, but not siRNA, may be impaired in cells with low DICER1
expression. The findings implicated a component of the RNA-interference
machinery, which regulates gene expression, in the pathogenesis of
ovarian cancer. Merritt et al. (2009) noted that 109 of the 111 samples
used in the 2008 study had serous histologic features, of which 93 were
high-grade and 16 low-grade tumors.
To explore the genetic origin of ovarian clear cell carcinoma, Jones et
al. (2010) determined the exomic sequences of 8 tumors after
immunoaffinity purification of cancer cells. Through comparative
analyses of normal cells from the same patients, Jones et al. (2010)
identified 4 genes that were mutated in at least 2 tumors. PIK3CA
(171834), which encodes a subunit of phosphatidylinositol-3 kinase, and
KRAS (190070), which encodes a well-known oncoprotein, had previously
been implicated in ovarian clear cell carcinoma. The other 2 mutated
genes were previously unknown to be involved in ovarian clear cell
carcinoma: PPP2R1A (605983) encodes a regulatory subunit of
serine/threonine phosphatase-2, and ARID1A (603024) encodes
adenine-thymine (AT)-rich interactive domain-containing protein 1A,
which participates in chromatin remodeling. The nature and pattern of
the mutations suggested that PPP2R1A functions as an oncogene and ARID1A
as a tumor suppressor gene. In a total of 42 ovarian clear cell
carcinomas, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A.
Jones et al. (2010) concluded that their results suggested that aberrant
chromatin remodeling contributes to the pathogenesis of ovarian clear
cell carcinoma.
Flesken-Nikitin et al. (2013) identified the hilum region of the mouse
ovary, the transitional (or junction) area between the ovarian surface
epithelium, mesothelium, and tubal (oviductal) epithelium, as a stem
cell niche of the ovarian surface epithelium (OSE). They found that
cells of the hilum OSE are cycling slowly and express stem and/or
progenitor cell markers ALDH1 (100640), LGR5 (606667), LEF1 (153245),
CD133 (604365), and CK6B (148042). These cells display long-term stem
cell properties ex vivo and in vivo, as shown by serial sphere
generation and long-term lineage-tracing assays. Importantly, the hilum
cells showed increased transformation potential after inactivation of
tumor suppressor genes Trp53 (191170) and Rb1 (614041), whose pathways
are altered frequently in the most aggressive and common type of human
epithelial ovarian cancer, high-grade serous adenocarcinoma.
Flesken-Nikitin et al. (2013) concluded that their study supported
experimentally the idea that susceptibility of transitional zones to
malignant transformation may be explained by the presence of stem cell
niches in these areas.
GENOTYPE/PHENOTYPE CORRELATIONS
Grindedal et al. (2010) performed a retrospective survival study of 144
women with ovarian cancer due to MMR mutations. Fifty-one (35.4%) had a
mutation in MLH1, 78 (54.2%) had a mutation in MSH2, and 15 (10.4%) had
a mutation in MSH6. The mean age of onset was 44.7 years, compared to
51.2 years in carriers of BRCA1 (113705) mutations with ovarian cancer
and 57.5 in carriers of BRCA2 (600185) mutations with ovarian cancer
(Risch et al., 2001). Most (81.5%) women with MMR mutations were
diagnosed at stage 1 or 2. Twenty-nine (20.1%) of 144 woman with
MMR-related ovarian cancer died of their ovarian cancer. The 5-, 10-,
20- and 30-year survival specific for deaths due to ovarian cancers were
82.7%, 80.6%, 78.0% and 71.5%, respectively. About 50% of the women
developed another cancer in the HNPCC/Lynch syndrome tumor spectrum. The
5-, 10-, 20-, and 30-year survival specific for deaths due to
HNPCC/Lynch syndrome-associated cancers were 79.2%, 75.7%, 68.4% and
47.3%, respectively. Overall, the survival for women with ovarian cancer
due to MMR mutations was better than for those with ovarian cancer due
to BRCA1/2 mutations, which is less than 40% at 10 years. The lifetime
risk of ovarian cancer in MMR mutation carriers was about 10% and the
risk of dying from ovarian cancer was 20%, yielding an overall risk of
dying from ovarian cancer of about 2% in MMR mutation carriers.
Grindedal et al. (2010) suggested that mutations in the MMR and BRCA1/2
genes may predispose to biologically different types of tumors.
ANIMAL MODEL
Dinulescu et al. (2005) developed a mouse model of ovarian cancer. A
recombinant adenoviral vector expressing an oncogenic Kras (190070)
allele within the ovarian surface epithelium resulted in the development
of benign epithelial lesions with a typical endometrioid glandular
morphology that did not progress to ovarian carcinoma; 7 of 15 mice
(47%) also developed peritoneal endometriosis (131200). When the Kras
mutation was combined with conditional deletion of Pten (601728), all
mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu
et al. (2005) stated that these were the first mouse models of
endometriosis and endometrioid adenocarcinoma of the ovary.
*FIELD* SA
Donnai and Warrell (1983)
*FIELD* RF
1. Auersperg, N.; Wong, A. S. T.; Choi, K.-C.; Kang, S. K.; Leung,
P. C. K.: Ovarian surface epithelium: biology, endocrinology, and
pathology. Endocr. Rev. 22: 255-288, 2001.
2. Blechschmidt, K.; Sassen, S.; Schmalfeldt, B.; Schuster, T.; Hofler,
H.; Becker, K.-F.: The E-cadherin repressor snail is associated with
lower overall survival of ovarian cancer patients. Brit. J. Cancer 98:
489-495, 2008.
3. Cancer Genome Atlas Research Network: Integrated genomic analyses
of ovarian carcinoma. Nature 474: 609-615, 2011. Note: Erratum:
Nature 490: 292 only, 2012.
4. Cesari, R.; Martin, E. S.; Calin, G. A.; Pentimalli, F.; Bichi,
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*FIELD* CS
Oncology:
Ovarian cancer;
Dysgerminoma;
Ovarian papillary adenocarcinoma;
Serous ovarian cystadenocarcinoma;
Breast cancer
Lab:
Frequent loss of heterozygosity at 6q24-q27
Inheritance:
Autosomal dominant
*FIELD* CN
Ada Hamosh - updated: 4/1/2013
Ada Hamosh - updated: 7/26/2012
Ada Hamosh - updated: 7/23/2012
Ada Hamosh - updated: 8/24/2011
Ada Hamosh - updated: 11/4/2010
Ada Hamosh - updated: 9/21/2010
Cassandra L. Kniffin - updated: 6/4/2010
George E. Tiller - updated: 3/2/2010
George E. Tiller - updated: 2/22/2010
Cassandra L. Kniffin - updated: 3/19/2009
Cassandra L. Kniffin - reorganized: 2/6/2009
Cassandra L. Kniffin - updated: 1/30/2009
Victor A. McKusick - updated: 3/13/1998
Victor A. McKusick - updated: 2/24/1998
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
mgross: 11/20/2013
carol: 10/1/2013
terry: 4/4/2013
alopez: 4/3/2013
terry: 4/1/2013
alopez: 10/3/2012
terry: 8/8/2012
alopez: 7/26/2012
terry: 7/23/2012
alopez: 8/26/2011
terry: 8/24/2011
alopez: 11/11/2010
terry: 11/4/2010
alopez: 9/23/2010
terry: 9/21/2010
wwang: 6/9/2010
ckniffin: 6/4/2010
wwang: 3/15/2010
terry: 3/2/2010
wwang: 2/24/2010
terry: 2/22/2010
terry: 6/3/2009
wwang: 3/20/2009
ckniffin: 3/19/2009
carol: 2/6/2009
terry: 2/6/2009
terry: 2/2/2009
ckniffin: 1/30/2009
carol: 3/17/2004
carol: 8/19/1999
carol: 5/12/1998
alopez: 3/13/1998
terry: 3/10/1998
dholmes: 2/24/1998
dholmes: 2/18/1998
mark: 7/30/1995
mimadm: 1/14/1995
carol: 9/8/1993
carol: 7/1/1992
supermim: 3/16/1992
carol: 3/8/1992
MIM
600098
*RECORD*
*FIELD* NO
600098
*FIELD* TI
*600098 RELATED RAS VIRAL ONCOGENE HOMOLOG 2; RRAS2
;;ONCOGENE RRAS2;;
TERATOCARCINOMA ONCOGENE TC21; TC21
read more*FIELD* TX
CLONING
The TC21 oncogene, a member of the RAS superfamily, was initially cloned
from a human teratocarcinoma cDNA library by PCR methods using
degenerate oligonucleotides corresponding to the conserved region of the
RAS genes (Drivas et al., 1990). Chan et al. (1994) found the same
oncogene when they generated an expression cDNA library from an ovarian
carcinoma (167000) line. They found, furthermore, that a single point
mutation substituting glutamine for leucine at position 72 was
responsible for activation of transforming properties. While the cDNA
clone possessed high transforming activity, the ovarian tumor genomic
DNA, which contained the mutated TC21 allele, failed to induce
transformed foci. Thus, expression cDNA cloning made it possible to
identify and isolate a human oncogene that had evaded detection by
conventional approaches.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the RRAS2
gene to chromosome 11pter-p15.5 (TMAP RH40056).
*FIELD* AV
.0001
OVARIAN CANCER, SOMATIC
RRAS2, LEU72GLN
Chan et al. (1994) identified a somatic leu72-to-gln (L72Q) mutation in
the TC21 gene in epithelial ovarian tumor tissue (167000) and
demonstrated that the mutation was associated with high transforming
activity.
*FIELD* RF
1. Chan, A. M.-L.; Miki, T.; Meyers, K. A.; Aaronson, S. A.: A human
oncogene of the RAS superfamily unmasked by expression cDNA cloning. Proc.
Nat. Acad. Sci. 91: 7558-7562, 1994.
2. Drivas, G. T.; Shih, A.; Coutavas, E.; Rush, M. G.; D'Eustachio,
P.: Characterization of four novel ras-like genes expressed in a
human teratocarcinoma cell line. Molec. Cell. Biol. 10: 1793-1798,
1990.
*FIELD* CD
Victor A. McKusick: 8/31/1994
*FIELD* ED
ckniffin: 01/30/2009
carol: 12/6/2001
alopez: 4/18/2001
mimadm: 9/23/1995
carol: 8/31/1994
*RECORD*
*FIELD* NO
600098
*FIELD* TI
*600098 RELATED RAS VIRAL ONCOGENE HOMOLOG 2; RRAS2
;;ONCOGENE RRAS2;;
TERATOCARCINOMA ONCOGENE TC21; TC21
read more*FIELD* TX
CLONING
The TC21 oncogene, a member of the RAS superfamily, was initially cloned
from a human teratocarcinoma cDNA library by PCR methods using
degenerate oligonucleotides corresponding to the conserved region of the
RAS genes (Drivas et al., 1990). Chan et al. (1994) found the same
oncogene when they generated an expression cDNA library from an ovarian
carcinoma (167000) line. They found, furthermore, that a single point
mutation substituting glutamine for leucine at position 72 was
responsible for activation of transforming properties. While the cDNA
clone possessed high transforming activity, the ovarian tumor genomic
DNA, which contained the mutated TC21 allele, failed to induce
transformed foci. Thus, expression cDNA cloning made it possible to
identify and isolate a human oncogene that had evaded detection by
conventional approaches.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the RRAS2
gene to chromosome 11pter-p15.5 (TMAP RH40056).
*FIELD* AV
.0001
OVARIAN CANCER, SOMATIC
RRAS2, LEU72GLN
Chan et al. (1994) identified a somatic leu72-to-gln (L72Q) mutation in
the TC21 gene in epithelial ovarian tumor tissue (167000) and
demonstrated that the mutation was associated with high transforming
activity.
*FIELD* RF
1. Chan, A. M.-L.; Miki, T.; Meyers, K. A.; Aaronson, S. A.: A human
oncogene of the RAS superfamily unmasked by expression cDNA cloning. Proc.
Nat. Acad. Sci. 91: 7558-7562, 1994.
2. Drivas, G. T.; Shih, A.; Coutavas, E.; Rush, M. G.; D'Eustachio,
P.: Characterization of four novel ras-like genes expressed in a
human teratocarcinoma cell line. Molec. Cell. Biol. 10: 1793-1798,
1990.
*FIELD* CD
Victor A. McKusick: 8/31/1994
*FIELD* ED
ckniffin: 01/30/2009
carol: 12/6/2001
alopez: 4/18/2001
mimadm: 9/23/1995
carol: 8/31/1994