title: Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer.
abstract: Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ~40% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with ≥6% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4%) patients with constitutive BRCA1 and three (0.5%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12-40%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen.
authors: Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
authors: Tamara
authors: T
authors: Hansmann
authors: Galyna
authors: G
authors: Pliushch
authors: Monika
authors: M
authors: Leubner
authors: Patricia
authors: P
authors: Kroll
authors: Daniela
authors: D
authors: Endt
authors: Andrea
authors: A
authors: Gehrig
authors: Sabine
authors: S
authors: Preisler-Adams
authors: Peter
authors: P
authors: Wieacker
authors: Thomas
authors: T
authors: Haaf
mesh_terms: D000328:Adult; D017668:Age of Onset; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; C448305:RAD51C protein, human