Journal Article

Genetic variants in epigenetic genes and breast cancer risk

Arancha Cebrian, Paul D. Pharoah, Shahana Ahmed, Santiago Ropero, Mario F. Fraga, Paula L. Smith, Don Conroy, Robert Luben, Barbara Perkins, Douglas F. Easton, Alison M. Dunning, Manel Esteller and Bruce A.J. Ponder

in Carcinogenesis

Volume 27, issue 8, pages 1661-1669
ISSN: 0143-3334
Published online February 2006 | e-ISSN: 1460-2180 | DOI:
Genetic variants in epigenetic genes and breast cancer risk

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Epigenetic events, resulting changes in gene expression capacity, are important in tumour progression, and variation in genes involved in epigenetic mechanisms might therefore be important in cancer susceptibility. To evaluate this hypothesis, we examined common variants in 12 genes coding for DNA methyltransferases (DNMT), histone acetyltransferases, histone deacetyltransferases, histone methyltrasferases and methyl-CpG binding domain proteins, for association with breast cancer in a large case–control study (N cases = 4474 and N controls = 4580). We identified 63 single nucleotide polymorphisms (SNPs) that efficiently tag all the known common variants in these genes, and are also expected to tag any unknown SNP in each gene. We found some evidence for association for six SNPs: DNMT3b-c31721t [P (2 df) = 0.007], PRDM2-c99243 t [P (2 df) = 0.03] and t105413c [P-recessive = 0.05], EHMT1-g-9441a [P (2df) = 0.05] and g41451t (P-trend = 0.04), and EHMT2-S237S [P (2df) = 0.04]. The most significant result was for DNMT3b-c31721t (P-trend = 0.124 after adjusting for multiple testing). However, there were three other results with P < 0.05. The permutation-based probability of this occurring by chance was 0.335. These significant SNPs were genotyped in 75 human cancer cell lines from different tumour types to assess if there was an association between them and six epigenetic measures. No statistically significant association was found. However, a trend was observed: homozygotes for the rare alleles of the EHMT1, EHMT2 and PRDM2 had a mean value for both trimethylation of K9 and K27 of histone H3 remarkably different to the homozygotes for the common alleles. Thus, these preliminary observations suggest the possible existence of a functional consequence of harbouring these genetic variants in histone methyltransferases, and warrant the design of larger epidemiological and biochemical studies to establish the true meaning of these findings.

Journal Article.  6961 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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