Genotypes and haplotypes of the methyl-CpG-binding domain 2 modify breast cancer risk dependent upon menopausal status

INTRODUCTION: MBD2, the gene encoding methyl-CpG-binding domain (MBD)2, is a major methylation related gene and functions as a transcriptional repressor that can specifically bind to the methylated regions of other genes. MBD2 may also mediate gene activation because of its potential DNA demethylase activity. The present case-control study investigated associations between two single nucleotide polymorphisms (SNPs) in the MBD2 gene and breast cancer risk. METHODS: DNA samples from 393 Caucasian patients with breast cancer (cases) and 436 matched control individuals, collected in a recently completed breast cancer case–control study conducted in Connecticut, were included in the study. Because no coding SNPs were found in the MBD2 gene, one SNP in the noncoding exon (rs1259938) and another in the intron 3 (rs609791) were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate cancer risk associated with the variant genotypes and the reconstructed haplotypes. RESULTS: The variant genotypes at both SNP loci were significantly associated with reduced risk among premenopausal women (OR = 0.41 for rs1259938; OR = 0.54 for rs609791). Further haplotype analyses showed that the two rare haplotypes (A-C and A-G) were significantly associated with reduced breast cancer risk (OR = 0.40, 95% CI = 0.20–0.83 for A-C; OR = 0.47, 95% CI = 0.26–0.84 for A-G) in premenopausal women. No significant associations were detected in the postmenopausal women and the whole population. CONCLUSION: Our results demonstrate a role for the MBD2 gene in breast carcinogenesis in premenopausal women. These findings suggest that genetic variations in methylation related genes may potentially serve as a biomarker in risk estimates for breast cancer

Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers

A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor-alpha (ERalpha). Previous investigation suggests that methylation of CpGs within the ERa promoter mediates repression of gene expression in some ERalpha-negative breast cancers. To determine if methylation of CpGs within the ERalpha promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ERalpha gene in 40 ERalpha-negative breast cancers, 20 of which were non BRCA1-linked and 20 BRCA1-linked. CpG methylation was evaluated by either methylation-sensitive restriction digest (HpaII), methylation-sensitive PCR (MSP), or direct sequencing of bisulfite-treated genomic DNA. Results from HpaII digests and MSP documented a high degree of methylation, the MSP data showing slightly higher methylation in the BRCA1-linked group. CpGs analysed by direct sequencing showed an overall average methylation of 25% among non BRCA1-linked cancers and 40% among BRCA1-linked cancers (P=0.0031). The most notable difference was found at five particular CpGs, each of which exhibited a greater than twofold increase in methylation in the BRCA1-linked group compared to the non BRCA1-linked group (P < 0.03 for each CpG). Methylation of certain critical CpGs may represent an important factor in transcriptional repression of the ERa gene in BRCA1-linked breast cancers