Panel sequencing of 264 candidate susceptibility genes and segregation analysis in a cohort of non-BRCA1, non-BRCA2 breast cancer families

Breast Cancer Res Treat. 2017 Dec;166(3):937-949. doi: 10.1007/s10549-017-4469-0. Epub 2017 Aug 24.


Purpose: The main aim of this study was to screen epigenetic modifier genes and known breast cancer driver genes for germline mutations in non-BRCA1/2 (BRCAx) breast cancer families in order to identify novel susceptibility genes of moderate-high penetrance.

Methods: We screened 264 candidate susceptibility genes in 656 index cases from non-BRCA1/2 families. Potentially pathogenic candidate mutations were then genotyped in all available family members for the assessment of co-segregation of the variant with disease in the family in order to estimate the breast cancer risks associated with these mutations. For 11 of the candidate susceptibility genes, we screened an additional 800 non-BRCA1/2 breast cancer cases and 787 controls.

Results: Only two genes, CHD8 and USH2A showed any evidence of an increased risk of breast cancer (RR = 2.40 (95% CI 1.0-7.32) and 2.48 (95% CI 1.11-6.67), respectively).

Conclusions: We found no convincing evidence that epigenetic modifier and known breast cancer driver genes carry germline mutations that increase breast cancer risk. USH2A is no longer regarded as a breast cancer driver gene and seems an implausible candidate given its association with Usher syndrome. However, somatic mutations in CHD8 have been recently reported, making it an even more promising candidate, but further analysis of CHD8 in very large cohorts of families or case-control studies would be required to determine if it is a moderate-risk breast cancer susceptibility gene.

Keywords: Breast cancer; Chromatin modification genes; Mutation; Segregation; Susceptibility gene.

MeSH terms

  • Adult
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • DNA-Binding Proteins / genetics
  • Epigenesis, Genetic / genetics*
  • Extracellular Matrix Proteins / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation
  • Humans
  • Middle Aged
  • Pedigree
  • Risk
  • Transcription Factors / genetics
  • Usher Syndromes / genetics*
  • Usher Syndromes / pathology


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • CHD8 protein, human
  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • Transcription Factors
  • USH2A protein, human