Individuals with germline mutations in BRCA1 have an elevated risk of developing breast cancer, and often display characteristic clinico-pathological features. We hypothesised that inactivation of BRCA1 by promoter methylation could occur as a germline or an early somatic event that predisposes to breast cancer with the phenotype normally associated with BRCA1 germline mutation. We examined cases of early onset breast cancer with tumours that showed BRCA1-like pathology but did not have detectable BRCA1 or BRCA2 germline mutations. Methylation levels were tested by several quantitative techniques including MethyLight, Methylation Sensitive - High Resolution Melting (MS-HRM) and a newly developed digital MS-HRM assay. In several patients, methylation of 1-10% of the BRCA1 alleles was detected in the peripheral blood DNA, consistent with up to 20% of cells having one methylated allele. Tumour DNAs from these patients were heavily methylated at BRCA1. These results demonstrate that in some cases of breast cancer, low level promoter methylation of BRCA1 by occurs in normal tissues of the body and is associated with the development of BRCA1-like breast cancer.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA