Inherited mutations in ovarian cancer - PALB2 and BARD1 are likely ovarian cancer susceptibility genes. B. Norquist1, M. I. Harrell1, M. F. Brady2, T. Walsh3, M. K. Lee3, S. Gulsuner3, Q. Yi3, S. Casadei3, S. Bernards1, S. A. Davidson4, R. S. Mannel5, P. A. DiSilvestro6, M. C. King3, M. J. Birrer7, E. M. Swisher1, 3 1) Department of Obstetrics and Gynecology, University of Washington, Seattle, WA; 2) Gynecologic Oncology Group Biostatistical Office, Roswell Park Cancer Institute, Buffalo, NY; 3) Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA; 4) Department of Obstetrics and Gynecology, University of Colorado, Denver, CO; 5) Department of Obstetrics and Gynecology, University of Oklahoma, Oklahoma City, OK; 6) Department of Obstetrics and Gynecology, Brown University, Providence, RI; 7) Dana-Farber/Harvard Cancer Center, Department of Medicine, Harvard Medical School, Boston, MA.
To determine the frequency and significance of germline mutations in cancer-associated genes, we evaluated 1889 women with epithelial ovarian, fallopian tube, and primary peritoneal cancer (OC). We sequenced germline DNA using the targeted capture and multiplex sequencing panel BROCA. OCs were ascertained from three sources, two phase III clinical trials in newly diagnosed advanced stage ovarian cancer (GOG 218, N=773; GOG 262, N=573) and a university-based gynecologic oncology tissue bank (N=543). Cases were not selected for age or family history. Mutation rates excluding CNVs were compared to population rates for European-Americans from the NHLBI GO Exome Sequencing Project (ESP), for which insertions and deletions of targeted genes were re-evaluated by hand. Only clearly damaging mutations were included. Of 1889 subjects, 381 (20%) had 390 germline mutations in cancer-associated genes. Of the 381 mutations carriers, 8 (2.1%) had more than one mutation, 278 (14.7%) had mutations in BRCA1 (182) or BRCA2 (96), and 109 (5.8%) had mutations in the following genes: BRIP1 (27), CHEK2 (13), RAD51D (11), PALB2 (11), ATM (11), RAD51C (10), NBN (9), TP53 (6), BARD1 (4), MSH6 (4), FAM175A (3), PMS2 (2), and MLH1 (1). Consistent with their role as ovarian cancer susceptibility genes, BRIP1, RAD51C, and RAD51D were significantly more frequently mutated in OC patients than in the ESP (all p<0.001). PALB2 and BARD1, which are not proven ovarian cancer genes, were also significantly more frequently mutated in OC (PALB2: OR=11.0, 95% CI [2.4, 50], p=0.0003; BARD1: OR=31.0, 95% CI [1.7, 577], p=0.02. ATM, NBN, CHEK2, and FAM175A mutations were not significantly more common in OC. Patients with BRCA2 mutations had significantly better progression-free survival (p=0.009) and overall survival (p=0.0005). BRCA2 carriers had more grade 4 neutropenia (p=0.04). Histologic subtype and primary site did not predict mutation status. Additional clinical data will be available at time of presentation regarding treatment response by mutation status. In summary, mutations in PALB2, BARD1, BRIP1, RAD51C, and RAD51D were more frequent in OC than in the ESP EA population. Mutation status affects treatment response and should be accounted for when designing and reporting clinical trials.
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