1. Panel sequencing of 264 candidate susceptibility genes and segregation analysis in a cohort of non-BRCA1, non-BRCA2 breast cancer families
- Author
-
Kayoko Tao, Hongyan Li, Sean V. Tavtigian, Nicola J. Camp, Kum Kum Khanna, Erin L. Young, Irene L. Andrulis, Bryony A. Thompson, Esther M. John, Igor V. Makunin, Jacqueline Lopez, David E. Goldgar, Georgia Chenevix-Trench, and Jun Li
- Subjects
0301 basic medicine ,Adult ,Risk ,Cancer Research ,Usher syndrome ,Breast Neoplasms ,Disease ,Biology ,medicine.disease_cause ,Article ,Epigenesis, Genetic ,03 medical and health sciences ,Breast cancer ,Germline mutation ,medicine ,Humans ,Genetic Predisposition to Disease ,skin and connective tissue diseases ,Gene ,Germ-Line Mutation ,Genetics ,BRCA2 Protein ,Mutation ,Extracellular Matrix Proteins ,BRCA1 Protein ,Middle Aged ,medicine.disease ,Penetrance ,Pedigree ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Female ,Usher Syndromes ,Transcription Factors - Abstract
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. 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. 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). 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.
- Published
- 2017