BRCA1 and BRCA2 MutationPrevalenceandClinical CharacteristicsofaPopulation-BasedSeriesof OvarianCancerCasesfromDenmark Marie Soegaard, 1 SusanneKrugerKjaer, 1,2 MarkCox, 3 EvaWozniak, 3 EstridHÖgdall, 1 Claus HÖgdall, 2 JanBlaakaer, 4 IanJ.Jacobs, 3 SimonA.Gayther, 3 and SusanJ. Ramus 3 Abstract Purpose: Toevaluatetheprevalenceof BRCA1 and BRCA2 mutationsandassociationswithclin- ical correlates of disease in a population-based series ofovariancancer cases from Denmark. Methods: DNA sequencing and multiplex ligation-dependent probe amplification analysis were usedtoanalyzethe BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer.We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors. Results: Deleterious BRCA1 or BRCA2 mutationswereidentifiedin26cases;thus,mutationsin these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations in Denmark.We identified several differences between mutation carriers and noncarriers: mutation carriers were diagnosed at a significantly early age (median, 49 and 61years, respectively; P = 0.0001); the frequency of BRCA1mutation carriers was 23% for womendiagnosed <40years,15%for40to49years,4%for50to59years,and2%for z60years (P =0.00002);ovariancancerincarrierswasdiagnosedatalaterstage( P =0.002)andtumors were of poorer grade (P = 0.0001); and first-degree relatives of mutation carriers had greater relative risks of both ovarian cancer [10.6 (95% confidence interval, 4.2-26.6); P < 0.0001] and breastcancer <60 years [8.7 (95% confidenceinterval, 3.0-25.0); P < 0.0001]. Conclusion: These data may have a significant effect on risk assessment and clinical manage- ment of individuals from Denmark who are predisposed to ovarian cancer because they carry a BRCA1 or BRCA2 mutation. Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy in the western world. The strongest known risk factor is a family history of the disease; an individual with a first-degree relative affected with ovarian cancer has a 3-fold increased risk of developing the disease (1). Two genes, BRCA1 and BRCA2 (2, 3), are responsible for the majority of families containing multiple cases of breast and ovarian cancer (4–6). The cumulative lifetime risks of ovarian cancer associated with these genes have been estimated as 40% to 50% for a BRCA1 mutation carrier and 20% to 30% in BRCA2 carriers (4, 7). There have been several studies reporting the prevalence of BRCA1 and BRCA2 mutations in ovarian cancer cases unselected for family history (8–13). Together, these studies suggest that mutations in these genes may cause 3% to 15% of all ovarian cancers. The first published study of 374 ovarian cancer cases from southern England, which analyzed just BRCA1 , identified truncating mutations in 3% of cases (8). Another larger study reported a higher prevalence (8%) in 977 patients from Canada (13). Less data are available for BRCA2 , but the Canadian study reported deleterious mutations for 5.9% of cases (13). There are several reports of BRCA1 and BRCA2 analysis in ovarian and breast cancer cases from some Scandinavian countries (Finland, Norway, Sweden, and Iceland; refs. 13–19), but the data from the Danish population are much more limited. The largest study of BRCA1 and BRCA2 mutations to date from Denmark is the analysis of 103 multifocal or bilateral early-onset breast cancers, which identified mutations in 20% of cases (20). There are no reports in the literature describing Human Cancer Biology Authors’Affiliations: 1 Institute of Cancer Epidemiology, Danish Cancer Society; 2 The Gynaecologic Clinic,The Juliane Marie Centre, Copenhagen, Denmark; 3 Translational Research Laboratory, University College London Elizabeth Garrett Anderson Institute forWomen’s Health, University College London, London, United Kingdom; and 4 Department of Gynaecology and Obstetrics, Aarhus UniversityHospital,Aarhus,Denmark Received11/2/07;revised3/6/08;accepted3/6/08. Grant support: Mermaid/Eve Appeal. This work was partly undertaken at University College London Hospital/University College London, which received a proportion of funding from the Department of Health’s National Institute of Health ResearchBiomedicalResearchCentresfundingscheme. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.This article must therefore be hereby marked advertisement in accordance with18U.S.C.Section1734solely toindicatethisfact. Requestsforreprints: Simon A. Gayther,Translational Research Laboratory, Elizabeth Garrett Anderson Institute forWomen’s Health, University College London,Windeyer Building, 46 Cleveland Street, LondonW1T 4JF, United Kingdom. Phone: 44-20-7679-9204; Fax: 44-20-7679-9687; E-mail: s.gayther@ ucl.ac.uk. F 2008AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-07-4806 www.aacrjournals.org ClinCancerRes2008;14(12)June15,2008 3761 Research. on April 5, 2016. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from