Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas

Clin Cancer Res. 2014 Feb 1;20(3):764-75. doi: 10.1158/1078-0432.CCR-13-2287. Epub 2013 Nov 15.

Abstract

Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain.

Experimental design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway.

Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation.

Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use
  • Carcinoma / genetics*
  • Carcinoma / mortality
  • Drug Resistance, Neoplasm / genetics*
  • Fallopian Tube Neoplasms / drug therapy
  • Fallopian Tube Neoplasms / genetics*
  • Fallopian Tube Neoplasms / mortality
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homologous Recombination / drug effects
  • Homologous Recombination / genetics*
  • Humans
  • Middle Aged
  • Mutation*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / mortality
  • Peritoneal Neoplasms / drug therapy
  • Peritoneal Neoplasms / genetics*
  • Peritoneal Neoplasms / mortality
  • Platinum Compounds / therapeutic use

Substances

  • Antineoplastic Agents
  • Platinum Compounds