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High frequency of allelic loss at the BRCA1 locus in ovarian cancers: clinicopathologic and molecular associations

      BRCA1 dysfunction may occur by different mechanisms that are rarely evaluated concomitantly. We aimed to analyze BRCA1 germline mutations, loss of heterozygosity (LOH) and promoter methylation in unselected ovarian carcinomas in the context of their clinicopathologic characteristics and other molecular changes. BRCA1 mutations were analyzed in 257 carcinomas using single-strand conformation polymorphism (SSCP), heteroduplex, and sequencing methods. LOH at the BRCA1 locus was screened for in 180 cancers. Methylation analysis was performed for 241 tumors using quantitative methylation specific PCR (qMSP). BRCA1 alterations, comprising germline mutations, allelic loss, and/or aberrant promoter methylation, were found in 77.6% (125/161) of ovarian carcinomas. Patients with germline mutations were younger than non-carriers (P < 0.0001). Germline mutations and LOH were associated with advanced stages (P=0.009, P < 0.0001), high tumor grade (P=0.005, P < 0.0001), and TP53 mutations (P=0.003, P < 0.0001, for mutations and LOH, respectively). LOH was also associated with the serous histological type (P=0.004) and PIK3CA amplification (P=0.003). Aberrant promoter methylation was associated with LOH (P=0.017) and absence of germline mutations (P=0.037). The high frequency of LOH at the BRCA1 locus suggests that LOH may be an important mechanism of BRCA1 deficiency in ovarian carcinomas. Tumors with various BRCA1 alterations have a similar phenotype of high-grade, high-stage carcinomas with frequent TP53 mutations.

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      References

        • Weberpals J.I.
        • Clark-Knowles K.V.
        • Vanderhyden B.C.
        Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway.
        J Clin Oncol. 2008; 26: 3259-3267
        • Prat J.
        • Ribe A.
        • Gallardo A.
        Hereditary ovarian cancer.
        Hum Pathol. 2005; 36: 861-870
        • Ramus S.J.
        • Gayther S.A.
        The contribution of BRCA1 and BRCA2 to ovarian cancer.
        Mol Oncol. 2009; 3: 138-150
        • Walsh C.S.
        • Ogawa S.
        • Scoles D.R.
        • et al.
        Genome-wide loss of heterozygosity and uniparental disomy in BRCA1/2-associated ovarian carcinomas.
        Clin Cancer Res. 2008; 14: 7645-7651
        • Lakhani S.R.
        • Manek S.
        • Penault-Llorca F.
        • et al.
        Pathology of ovarian cancers in BRCA1 and BRCA2 carriers.
        Clin Cancer Res. 2004; 10: 2473-2481
        • Werness B.A.
        • Ramus S.J.
        • Whittemore A.S.
        • et al.
        Histopathology of familial ovarian tumors in women from families with and without germline BRCA1 mutations.
        Hum Pathol. 2000; 31: 1420-1424
        • Wang C.
        • Horiuchi A.
        • Imai T.
        • et al.
        Expression of BRCA1 protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and allelic loss of the BRCA1 gene.
        J Pathol. 2004; 202: 215-223
        • Wilson C.A.
        • Ramos L.
        • Villasenor M.R.
        • et al.
        Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas.
        Nat Genet. 1999; 21: 236-240
        • Zheng W.
        • Luo F.
        • Lu J.J.
        • et al.
        Reduction of BRCA1 expression in sporadic ovarian cancer.
        Gynecol Oncol. 2000; 76: 294-300
        • Thrall M.
        • Gallion H.H.
        • Kryscio R.
        • et al.
        BRCA1 expression in a large series of sporadic ovarian carcinomas: a Gynecologic Oncology Group study.
        Int J Gynecol Cancer. 2006; 16: 166-171
        • Brozek I.
        • Ochman K.
        • Debniak J.
        • et al.
        Loss of heterozygosity at BRCA1/2 loci in hereditary and sporadic ovarian cancers.
        J Appl Genet. 2009; 50: 379-384
        • Clark-Knowles K.V.
        • Garson K.
        • Jonkers J.
        • et al.
        Conditional inactivation of Brca1 in the mouse ovarian surface epithelium results in an increase in preneoplastic changes.
        Exp Cell Res. 2007; 313: 133-145
        • Aghmesheh M.
        • Nesland J.M.
        • Kaern J.
        • et al.
        No differences in p53 mutation frequencies between BRCA1-associated and sporadic ovarian cancers.
        Gynecol Oncol. 2004; 95: 430-436
        • Buller R.E.
        • Lallas T.A.
        • Shahin M.S.
        • et al.
        The p53 mutational spectrum associated with BRCA1 mutant ovarian cancer.
        Clin Cancer Res. 2001; 7: 831-838
        • Rhei E.
        • Bogomolniy F.
        • Federici M.G.
        • et al.
        Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers.
        Cancer Res. 1998; 58: 3193-3196
        • Tong D.
        • Kucera E.
        • Schuster E.
        • et al.
        Loss of heterozygosity (LOH) at p53 is correlated with LOH at BRCA1 and BRCA2 in various human malignant tumors.
        Int J Cancer. 2000; 88: 319-322
        • Villeneuve J.B.
        • Silverman M.B.
        • Alderete B.
        • et al.
        Loss of markers linked to BRCA1 precedes loss at important cell cycle regulatory genes in epithelial ovarian cancer.
        Genes Chromosomes Cancer. 1999; 25: 65-69
        • Tavassoli F.A.
        • Devilee P.
        Pathology and genetics of tumours of the breast and female genital organs.
        IARC Press, Lyon2003
        • Barber H.R.
        • Sommers S.C.
        • Synder R.
        • et al.
        Histologic and nuclear grading and stromal reactions as indices for prognosis in ovarian cancer.
        Am J Obstet Gynecol. 1975; 121: 795-807
        • Creasman W.
        Announcement, FIGO stages 1988, revisions.
        Gynecol Oncol. 1989; 35: 125-127
        • Dansonka-Mieszkowska A.
        • Ludwig A.H.
        • Kraszewska E.
        • et al.
        Geographical variations in TP53 mutational spectrum in ovarian carcinomas.
        Ann Hum Genet. 2006; 70: 594-604
        • Kolasa I.K.
        • Rembiszewska A.
        • Felisiak A.
        • et al.
        PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients.
        Cancer Biol Ther. 2009; 8: 21-26
        • Kolasa I.K.
        • Rembiszewska A.
        • Janiec-Jankowska A.
        • et al.
        PTEN mutation, expression and LOH at its locus in ovarian carcinomas. Relation to TP53, K-RAS and BRCA1 mutations.
        Gynecol Oncol. 2006; 103: 692-697
        • Esteller M.
        • Silva J.M.
        • Dominguez G.
        • et al.
        Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors.
        J Natl Cancer Inst. 2000; 92: 564-569
        • Eads C.A.
        • Lord R.V.
        • Wickramasinghe K.
        • et al.
        Epigenetic patterns in the progression of esophageal adenocarcinoma.
        Cancer Res. 2001; 61: 3410-3418
        • Press J.Z.
        • De Luca A.
        • Boyd N.
        • et al.
        Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities.
        BMC Cancer. 2008; 8: 17
        • Majdak E.J.
        • Debniak J.
        • Milczek T.
        • et al.
        Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma.
        Cancer. 2005; 104: 1004-1012
        • Menkiszak J.
        • Gronwald J.
        • Gorski B.
        • et al.
        Hereditary ovarian cancer in Poland.
        Int J Cancer. 2003; 106: 942-945
        • Gorski B.
        • Byrski T.
        • Huzarski T.
        • et al.
        Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.
        Am J Hum Genet. 2000; 66: 1963-1968
        • Janiszewska H.
        • Haus O.
        • Lauda-Swieciak A.
        • et al.
        Frequency of three BRCA1 gene founder mutations in breast/ovarian cancer families from the Pomerania-Kujawy region of Poland.
        Clin Genet. 2003; 64: 502-508
        • Bowtell D.D.
        The genesis and evolution of high-grade serous ovarian cancer.
        Nat Rev Cancer. 2010; 10: 803-808
        • Shih I.E.M.
        • Kurman R.J.
        Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis.
        Am J Pathol. 2004; 164: 1511-1518
        • Russell P.A.
        • Pharoah P.D.
        • De Foy K.
        • et al.
        Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers.
        Int J Cancer. 2000; 87: 317-321
        • Geisler J.P.
        • Hatterman-Zogg M.A.
        • Rathe J.A.
        • et al.
        Frequency of BRCA1 dysfunction in ovarian cancer.
        J Natl Cancer Inst. 2002; 94: 61-67
        • Jeng Y.M.
        • Cai-Ng S.
        • Li A.
        • et al.
        Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation.
        Oncogene. 2007; 26: 6160-6166
        • Werness B.A.
        • Parvatiyar P.
        • Ramus S.J.
        • et al.
        Ovarian carcinoma in situ with germline BRCA1 mutation and loss of heterozygosity at BRCA1 and TP53.
        J Natl Cancer Inst. 2000; 92: 1088-1091
        • Baldwin R.L.
        • Nemeth E.
        • Tran H.
        • et al.
        BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study.
        Cancer Res. 2000; 60: 5329-5333
        • Ramus S.J.
        • Bobrow L.G.
        • Pharoah P.D.
        • et al.
        Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours.
        Genes Chromosomes Cancer. 1999; 25: 91-96
        • Zweemer R.P.
        • Shaw P.A.
        • Verheijen R.M.
        • et al.
        Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations.
        J Clin Pathol. 1999; 52: 372-375
        • Jazaeri A.A.
        • Yee C.J.
        • Sotiriou C.
        • et al.
        Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers.
        J Natl Cancer Inst. 2002; 94: 990-1000
        • Ramus S.J.
        • Pharoah P.D.
        • Harrington P.
        • et al.
        BRCA1/2 mutation status influences somatic genetic progression in inherited and sporadic epithelial ovarian cancer cases.
        Cancer Res. 2003; 63: 417-423