Abstract
IntroductionIndividuals with germline mutations in the BRCA1 gene have an elevated risk of developing breast cancer, and often display characteristic clinicopathological 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.MethodsWe examined seven cases from breast-ovarian cancer families with tumours that showed BRCA1-like pathology but did not have detectable BRCA1 or BRCA2 germline mutations present. 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.ResultsIn one patient, methylation of 10% of the BRCA1 alleles was detected in the peripheral blood DNA, consistent with 20% of cells having one methylated allele. Buccal mucosa DNA from this individual displayed approximately 5% BRCA1 methylation. In two other patients, methylation of BRCA1 was detected in the peripheral blood at significantly lower but still readily detectable levels (approximately 1%). Tumour DNAs from these three patients were heavily methylated at BRCA1. The other patients had no detectable BRCA1 methylation in their peripheral blood. One of seven age-matched controls showed extremely low levels of methylation in their peripheral blood (approximately 0.1%).ConclusionThese results demonstrate that in some cases of breast cancer, low-level promoter methylation of BRCA1 occurs in normal tissues of the body and is associated with the development of BRCA1-like breast cancer.
Highlights
Individuals with germline mutations in the BRCA1 gene have an elevated risk of developing breast cancer, and often display characteristic clinicopathological features
Individuals used in the study were enrolled in the Kathleen Cuningham Consortium for Research in Familial Breast Cancer. kConFab identified seven breast cancer cases (KCF1-7) with BRCA1-like features for analysis. kConFab provided DNA extracted from peripheral blood leukocytes from each case and DNA from buccal mucosa of patient KCF3
Map of the BRCA1 promoter region studied by the MethyLight and methylation-sensitive high resolution melting (MS-HRM) assays
Summary
Individuals with germline mutations in the BRCA1 gene have an elevated risk of developing breast cancer, and often display characteristic clinicopathological features. In 1994, BRCA1 was identified as the first major gene associated with familial breast cancer predisposition [1]. Since many inactivating mutations in BRCA1 have been identified as breast cancer predisposition alleles. The majority of breast cancers that exhibit a BRCA1-like phenotype do not harbour detectable germline mutations in BRCA1. Some of this discordance may be due to epigenetic defects in breast cancer susceptibility genes such as BRCA1 contributing to breast cancer predisposition
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