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

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

Abstract

Background: 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.

Methods: 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.

Results: 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)).

Conclusions: 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.

Publication types

  • Comparative Study
  • 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
  • Carcinoma, Ovarian Epithelial
  • Cell Cycle Proteins / genetics*
  • DNA-Binding Proteins / genetics*
  • European Continental Ancestry Group
  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Middle Aged
  • Mutation, Missense
  • Neoplasms, Glandular and Epithelial / genetics*
  • Neoplasms, Glandular and Epithelial / mortality
  • Nuclear Proteins / genetics*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / mortality
  • Predictive Value of Tests
  • RNA Helicases / genetics*
  • Risk
  • Tumor Suppressor Proteins / genetics*
  • Ubiquitin-Protein Ligases / genetics*
  • United States / epidemiology

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • NBN protein, human
  • Nuclear Proteins
  • PALB2 protein, human
  • Tumor Suppressor Proteins
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases
  • BRIP1 protein, human
  • RNA Helicases