Stevens Victoria L, McCullough Marjorie L, Pavluck Alexandre L, Talbot Jeffrey T, Feigelson Heather S, Thun Michael J, Calle Eugenia E
Department of Epidemiology and Surveillance Research, American Cancer Society, Northeastern, Atlanta, GA 30329, USA.
Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1140-7. doi: 10.1158/1055-9965.EPI-06-1037.
The interconversion of folates by the one-carbon metabolism pathway is essential for the synthesis of precursors used in DNA synthesis, repair, and methylation. Perturbations in this pathway can disrupt these processes and are hypothesized to facilitate carcinogenesis. We investigated associations of 25 candidate polymorphisms in nine one-carbon metabolism genes with risk of postmenopausal breast cancer using 502 cases and 505 controls from the Cancer Prevention II Nutrition Cohort. Four single nucleotide polymorphisms (SNP) in three different genes were significantly associated with breast cancer. The nonsynonymous R134K SNP in methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthase [MTHFD1; odds ratio (OR), 1.40; 95% confidence interval (95% CI), 1.06-1.85 for CT + TT] and an intronic SNP in formyltetrahydrofolate dehydrogenase (FTHFD; OR, 2.23; 95% CI, 1.09-4.54 for CC) were associated with a significant increase in risk. Significantly decreased risk was associated with an intronic SNP in FTHFD (OR, 0.75; 95% CI, 0.58-0.98 for CT + CC) and the A360A SNP in cystathionine beta-synthase (CBS; OR, 0.63; 95% CI, 0.41-0.96 for TT). The presence of at least one variant from both the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C SNPs was also associated with increased risk (OR, 2.16; 95% CI, 1.34-3.48 for 677 CT + TT/1,298 AC + CC). Investigations into interactions of the associated SNPs with each other and with dietary factors yielded inconclusive results. Our findings indicate that genetic variation in multiple one-carbon metabolism genes may influence risk of postmenopausal breast cancer and may involve changes in methyl donor synthesis. However, larger studies are needed to further examine gene/gene and gene/diet interactions in this pathway.
通过一碳代谢途径进行的叶酸相互转化对于DNA合成、修复和甲基化中使用的前体合成至关重要。该途径的紊乱会破坏这些过程，并被认为会促进癌症发生。我们使用癌症预防II营养队列中的502例病例和505例对照，研究了九个一碳代谢基因中的25个候选多态性与绝经后乳腺癌风险的关联。三个不同基因中的四个单核苷酸多态性（SNP）与乳腺癌显著相关。亚甲基四氢叶酸脱氢酶/亚甲基四氢叶酸环化水解酶/甲酰四氢叶酸合酶[MTHFD1；优势比（OR），1.40；95%置信区间（95%CI），CT + TT为1.06 - 1.85]中的非同义R134K SNP和甲酰四氢叶酸脱氢酶（FTHFD；OR，2.23；CC的95%CI，1.09 - 4.54）中的一个内含子SNP与风险显著增加相关。FTHFD中的一个内含子SNP（CT + CC的OR，0.75；95%CI，0.58 - 0.98）和胱硫醚β-合酶（CBS）中的A360A SNP（TT的OR，0.63；95%CI，0.41 - 0.96）与风险显著降低相关。亚甲基四氢叶酸还原酶（MTHFR）C677T和A1298C SNP中至少存在一个变体也与风险增加相关（677 CT + TT/1,298 AC + CC的OR，2.16；95%CI，1.34 - 3.48）。对相关SNP之间以及与饮食因素的相互作用的研究结果尚无定论。我们的研究结果表明，多个一碳代谢基因的遗传变异可能会影响绝经后乳腺癌的风险，并且可能涉及甲基供体合成的变化。然而，需要更大规模的研究来进一步研究该途径中的基因/基因和基因/饮食相互作用。
