Oral Presentation 25th Lorne Cancer Conference 2013

Somatic And Germline Mutations In Homologous Recombination Genes Predict Outcomes In Ovarian, Fallopian Tube, And Peritoneal Carcinomas. (#22)

Kathryn Pennington 1 , Tom Walsh 1 , Ming Lee 1 , Christopher Pennil 1 , Maria Harrell 1 , Kathy Agnew 1 , Mara Rendi 1 , Rochelle Garcia 1 , Mary-Claire King 1 , Elizabeth Swisher 1
  1. University of Washington, Seattle, WA, United States

Objectives:   We wanted to determine if germline and somatic mutations in the homologous recombination (HR) DNA repair genes impact outcomes of primary therapy for women with ovarian cancer.

Methods: We performed targeted capture and massively parallel sequencing on neoplastic and paired germline DNA from 394 ovarian, fallopian tube, and peritoneal carcinomas, including 331 primary and 63 recurrent cancers.  We sequenced both coding and non-coding regions of 30 tumor suppressor genes, including BRCA1, BRCA2, and 13 other HR genes using targeted capture and massively parallel genomic sequencing. Deletions and duplications of exons were detected by a combination of depth of coverage and split read analysis and supplemented with additional alignments generated by SLOPE.  Isolated deletion of the entire gene (LOH) was not counted as a deleterious HR event. All frameshift, nonsense, missense, or splice site mutations predicted to be deleterious to protein function were validated by PCR amplification and Sanger sequencing.

Results: Considering all 30 genes, deleterious germline mutations were identified in 94 of 371 women (25.3%), and 89 (24.0%) had mutations  in HR genes, 63 in BRCA1 or BRCA2  and 26 in other HR genes including BARD1, BRIP1, CHEK1, CHEK2, FAM175A, NBN, PALB2, RAD50, RAD51C, and RAD51D. Somatic HR mutations were identified in 35 cases (9.4%) including ATM, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, RAD50, and RAD51C. 118 (31.8%) cases had either a germline and/or somatic HR mutation. Primary platinum sensitivity was significantly associated with having a germline (P=.04) or somatic (P=.04) mutation (P=.009 considering germline and somatic mutations together).  For primary cancers, overall survival was significantly better for women with either a somatic or germline mutation (62 vs. 44 months, HR1.6, 95% CI 1.2-2.1). In 23 cases for which we had paired primary and recurrent neoplasms, 3 pairs had six different somatic HR mutations. In two cases somatic mutations were similarly identified in both primary and recurrence, while in 1 case, 2 of 4 somatic mutations were discordant.

Conclusions: Having a germline or somatic mutation in an HR gene correlates with a greater likelihood of primary platinum sensitivity and better overall survival. We predict these cases would be the ones most likely to benefit from the addition of a PARP inhibitor to the therapeutic regimen.