Germline DNA Methylation Associated with Breast Cancer Predisposition

Understanding and explaining hereditary predisposition to cancer has focused on the genetic etiology of the disease. However, mutations in known genes associated with breast cancer such as BRCA1 and BRCA2 account for less than 25% of familial cases of breast cancer. Heritable epigenetic modifications, in the form of hypermethylated MLH1 promoter alleles, have recently been shown to promote hereditary nonpolyposis colorectal cancer. We investigated the potential for an epigenetic basis for hereditary breast cancer by performing deep bisulfite sequencing of CpG islands and known promoter regions in germline DNA from 100 familial or early-onset breast or ovarian cancer patients.]]> The cohort was selected from patients who visited Stanford Cancer Genetics Clinic between 2004 and 2013. Out of a total of 983 patients, 443 were affected. Samples were classified by the likelihood of hereditary breast cancer predisposition based on the age of diagnosis, type of cancer, number of cancer diagnoses, and family history of cancer. 100 affected patients were selected for this study, all of whom had up to 6 alterations detected in clinical panel testing. 77 patients had VUS or benign alterations, and 23 patients had pathogenic or likely pathogenic mutation in one of these genes: ATM, BRCA1, BRCA2, CHEK2, MLH1, MSH2, MUTYH, PALB2, PMS2, or RAD51C. 91 had breast -/+ other cancers, 6 had ovarian -/+ other cancers and 3 had other cancers with extensive family history of breast or ovarian cancer. Age of onset varied between 18 and 61.]]>