Journal Article

Constitutive promoter methylation of <i>BRCA1</i> and <i>RAD51C</i> in patients with familial ovarian cancer and early-onset sporadic breast cancer

Tamara Hansmann, Galyna Pliushch, Monika Leubner, Patricia Kroll, Daniela Endt, Andrea Gehrig, Sabine Preisler-Adams, Peter Wieacker and Thomas Haaf

in Human Molecular Genetics

Volume 21, issue 21, pages 4669-4679
Published in print November 2012 | ISSN: 0964-6906
Published online July 2012 | e-ISSN: 1460-2083 | DOI:

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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.

Journal Article.  7363 words.  Illustrated.

Subjects: Genetics and Genomics

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