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

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer

The abnormality of DNA methylation is involved in tumour progression, and thus has a modulating effect on clinical outcome of cancer patients. In this study, we measured the mRNA expression levels of three methylation-regulating genes (DNMT1, DNMT3b, and MBD2) in 148 tumour samples from patients with non-small cell lung cancer (NSCLC) using quantitative real-time polymerase chain reaction and then determined their prognostic values. Our data showed that the high level of DNMT1 expression was significantly associated with an increased risk of death in all NSCLC patients (hazard ratio (HR), 1.74; 95% confidence interval (95% CI), 1.04–2.90). However, the high level of DNMT3b expression was significantly associated with poor prognosis only in young patients (<65 years). The high level of MBD2 expression had a significantly reduced risk for death only in male patients and in squamous cell lung carcinoma (SQLC) patients. All three combination groups with DNMT1 and DNMT3b, DNMT1 and MBD2 or DNMT3b and MBD2 revealed significant combined effects in male patients and SQLC patients. Our results suggest that DNMT1, DNMT3b, and MBD2 may play important roles in modulating NSCLC patient survival and thus be useful for identifying NSCLC patients who would benefit most from aggressive therapy

Inhibition of Soluble Tumor Necrosis Factor Ameliorates Synaptic Alterations and Ca2+ Dysregulation in Aged Rats

The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4–6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling. Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca2+ channel (VSCC) activity in hippocampal CA1 neurons. The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling