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Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-.....
Abstract
Genetic defects in breast cancer susceptibility genes, most importantly BRCA1 and BRCA2 account for approximately 40% of hereditary breast and ovarian cancers. 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 9 (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 breast cancer, and familial cases, in particular 4 (10%) of 39 patients with ovarian cancer. Hypermethylation was always confined to one of the two parental alleles in a subset (1240%) 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 breast and ovarian cancer should include an epimutation screen.
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