Document Detail


Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer.
MedLine Citation:
PMID:  22843497     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Tamara Hansmann; Galyna Pliushch; Monika Leubner; Patricia Kroll; Daniela Endt; Andrea Gehrig; Sabine Preisler-Adams; Peter Wieacker; Thomas Haaf
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-27
Journal Detail:
Title:  Human molecular genetics     Volume:  21     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2013-04-03     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  4669-79     Citation Subset:  IM    
Affiliation:
Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Adult
Age of Onset
BRCA1 Protein / genetics*
Breast Neoplasms / genetics*,  pathology
Cell Transformation, Neoplastic
DNA Methylation / genetics*
DNA-Binding Proteins / genetics*
Epigenesis, Genetic
Female
Gene Silencing
Genetic Predisposition to Disease
Humans
Mutation
Ovarian Neoplasms / genetics*,  pathology
Promoter Regions, Genetic
Chemical
Reg. No./Substance:
0/BRCA1 Protein; 0/BRCA1 protein, human; 0/DNA-Binding Proteins; 0/RAD51C protein, human
Comments/Corrections

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