Prevalence of BRCA1 Mutations in Familial and Sporadic Greek Ovarian Cancer Cases Alexandra V. Stavropoulou 1 , Florentia Fostira 1 , Maroulio Pertesi 1 , Marianthi Tsitlaidou 1 , Gerassimos E. Voutsinas 2 , Olga Triantafyllidou 1 , Aristotelis Bamias 3 , Meletios A. Dimopoulos 3 , Eleni Timotheadou 4 , Dimitrios Pectasides 5 , Christos Christodoulou 6 , George Klouvas 6 , Christos Papadimitriou 3 , Thomas Makatsoris 7 , George Pentheroudakis 8 , Gerasimos Aravantinos 9 , Vassilis Karydakis 10 , Drakoulis Yannoukakos 1 , George Fountzilas 4 , Irene Konstantopoulou 1 * 1 Molecular Diagnostics Laboratory, INRaSTES, National Center for Scientific Research ‘‘Demokritos’’, Athens, Greece, 2 Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biosciences and Applications, National Center for Scientific Research ‘‘Demokritos’’, Athens, Greece, 3 Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece, 4 Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece, 5 Oncology Section, Second Department of Internal Medicine, ‘‘Hippokration’’ Hospital, Athens, Greece, 6 Second Department of Medical Oncology, ‘‘Metropolitan’’ Hospital, Piraeus, Greece, 7 Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece, 8 Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece, 9 Second Department of Medical Oncology, ‘‘Agii Anargiri’’ Cancer Hospital, Athens, Greece, 10 1st Department of Surgery, Rhodes General Hospital, Rhodes, Greece Abstract Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23–24 and exon 24). In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6%) of familial cancer cases and in 27/592 (4.6%) of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%). The majority of BRCA1 carriers (71.2%) presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer. Citation: Stavropoulou AV, Fostira F, Pertesi M, Tsitlaidou M, Voutsinas GE, et al. (2013) Prevalence of BRCA1 Mutations in Familial and Sporadic Greek Ovarian Cancer Cases. PLoS ONE 8(3): e58182. doi:10.1371/journal.pone.0058182 Editor: Paolo Peterlongo, IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Italy Received November 26, 2012; Accepted January 31, 2013; Published March 11, 2013 Copyright: ß 2013 Stavropoulou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: reena@rrp.demokritos.gr Introduction Ovarian cancer is one of the highest mortality rated malignan- cies, an aspect mainly attributed to the advanced stage at diagnosis. Although new predisposing genes have been identified lately, the important players to ovarian cancer susceptibility are still the known BRCA1 and BRCA2 genes. Carriers of inherited mutations in BRCA1 and BRCA2 genes face a lifetime risk of ovarian cancer of 35–60% (average age of diagnosis 50 years) and 12–25% (average age of diagnosis 60 years) respectively, and also an elevated risk of fallopian tube and peritoneal carcinomas [1–3]. BRCA1 and BRCA2-associated ovarian malignancies have a distinct clinical phenotype, the majority of which being high-grade serous, advanced stage carcinomas [4], while generally are being associated with overall longer survival [5,6]. Moreover, the BRCA1/2 mutation status of an ovarian cancer patient can be an important aspect in regards to the decision of chemotherapy; BRCA1/2 carriers show increased sensitivity to platinum-based therapy [6,7], as well as to poly-ADP-ribose polymerase inhibitors [8]. Hereditary ovarian cancer can also occur in the context of Lynch syndrome, which is caused by inherited germline mutations within the MMR genes. The cumulative risk of ovarian cancer in MMR mutation carriers is estimated to be 10%, while histolog- ically these tumours are of the endometrioid subtype in most cases [9]. Hereditary ovarian cancer is probably underestimated, since recent studies highlight new susceptibility genes (RAD51C, RAD51D, PALB2) that might predispose for ovarian cancer, but their exact prevalence is still under investigation [10–13]. Up-to date sequencing technologies that provide the opportunity to test massively multiple targeted genes have been already applied in PLOS ONE | www.plosone.org 1 March 2013 | Volume 8 | Issue 3 | e58182