Polymorphisms of MTHFD,plasma homocysteine levels, and risk of gastric cancer in ahigh-risk Chinese population

Purpose:Accumulative evidence suggests that folate has a protective effect on gastric cancer. The methylenetetrahyd-rofolate dlehydrogenase(MTHFD) plays an important role in folate and homocysteine metabolisms, and polymorphisms of MTHFD may result in disturbance of the folate-mediated homocysteine pathway. The aim of this study is to test the hypothesis that genetic variants of MTHFD and plasma homocysteine levels are associated with risk of gastric cancer and modulated by genotypes of methylenetetrahydrofolate reductase(MTHFR). Experimental Design: We genotyped G1958A and T401C in MTHFD and C677T in MTHFR and detected total plasma homocysteine(tHcy) levels in a case-control study of 589 gastric cancer cases and 635 cancer-free controls in a high-risk Chinese population. Results:The variant genotypes of MTHFD 1958AA and 401CC were associated with a significantly increased risk of gastric canceradjusted odds ratio(OR), 2.05; 95% confidence interval(95% CI),1.34-3.13 for 1958AA; adjusted OR,1.43; 95% CI,1.14-1.80 for 401CC compared with 1958GG/GA and 401TT/TC genotypes, respectively. Both of the effects were more evident in the subjects carrying MTHFR 677CT/TT genotypes. The average tHcy level was significantly higher in gastric cancer cases than in controls(P < 0.01), and the upper quartile of tHcy (> 13.6 mu mol/L) was associated with an 82% significantly increased risk of gastric cancer, compared with the lowest quartile of tHcy(<= 8.0 pmol/L;adjusted OR,1.82; 95% CI,1.20-2.75). Conclusions:The strong associations between MTHFD variants and the plasma tHcy levels and gastric cancer risk suggest, for the first time, a possible gene-environment interaction between genetic variants of folate-metabolizing genes and high tHcy levels in gastric carcinogenesis.

Common non-synonymous polymorphisms in the BRCA1 Associated RING Domain (BARD1) gene are associated with breast cancer susceptibility:a case-control analysis

The BRCA1 Associated RING Domain(BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. BARD1 plays a crucial role in tumor repression, along with its heterodimeric partner BRCA1. In the current study, we tested the hypothesis that common non-synonymous polymorphisms in BARD1 are associated with breast cancer susceptibility in a case-control study of 507 patients with incident breast cancer and 539 frequency-matched cancer-free controls in Chinese women. We genotyped all three common(minor allele frequency (MAF) > 0.10) non-synonymous polymorphisms(Pro24Ser, Arg378Ser, and Val507Met) in BARD1. We found that the BARD1 Pro24Ser variant genotypes(24Pro/Ser and 24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, compared with their wild-type homozygotes, respectively. Furthermore, a significant locus-locus interaction was evident between Pro24Ser and Arg378Ser (P-int = 0.032). Among the 378Ser variant allele carriers, the 24Pro/Pro wild-type homozygote was associated with a significantly increased breast cancer risk (adjusted OR = 1.81, 95% CI = 1.11-2.95), but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had a significantly decreased risk(adjusted OR = 0.74, 95% CI = 0.56-0.99). In stratified analysis, this locus-locus interaction was more evident among subjects without family cancer history, those with positive estrogen receptor (ER) and individuals with negative progesterone receptor(PR). These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.