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J Natl Cancer Inst. 2015 Aug 27;107(11). pii: djv214. doi: 10.1093/jnci/djv214. Print 2015 Nov.

Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.

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Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA (SJR, MPI, CKE, DC, SAG); CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK (HS, ED, JPT, PH, JA, PDPP); Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, London, UK (ANR, LF, AGM, JH, SP, CA, UM, IJJ); Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (DB, ACA); Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia (DDB, KA, GM, AOCSSG); Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia (DDB); Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia (DDB, GM); Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK (DDB); Westmead Millennium Institute, Westmead Hospital, Sydney, Australia (AOCSSG); The QIMR Berghofer Medical Research Institute, Brisbane, Australia (AOCSSG); Department of Health Sciences Research, Mayo Clinic, Rochester, MN (MSC, JMC, ELG); Department of Biostatistics, University of Kansas Medical Center, Andover, KS (BLF); Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK (MJL); Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY (SP, SL, KO); Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY (LSC, KBM); Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA (WS, VM, ASW); Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center (JL, BYK); Gynaecology Research Unit, Hannover Medical School, Hannover, Germany (NB, TD); Radiation Oncology Research Unit, Hannover Medical School, Hannover,



Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.


Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.


We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).


Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.

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