Shen Jing, Terry Mary Beth, Gammon Marilie D, Gaudet Mia M, Teitelbaum Susan L, Eng Sybil M, Sagiv Sharon K, Neugut Alfred I, Santella Regina M
Department of Environmental Health Sciences, Columbia University, New York, NY 10032, USA.
Carcinogenesis. 2005 Dec;26(12):2131-7. doi: 10.1093/carcin/bgi179. Epub 2005 Jul 13.
O(6)-methylguanine DNA methyl-transferase (MGMT) is the only known critical gene involved in cellular defense against alkylating agents in the DNA direct reversal repair (DRR) pathway. Three single nucleotide polymorphism (SNP) coding for non-conservative amino acid substitutions have been identified [C250T (Leu84Phe), A427G (Ile143Val) and A533G (Lys178Arg)]. To examine the importance of the DRR pathway in risk for breast cancer and the potential interaction with cigarette smoking and dietary antioxidants, we genotyped for these variants using biospecimens from the Long Island Breast Cancer Study Project. Genotyping was performed by a high throughput assay with fluorescence polarization and included 1067 cases and 1110 controls. Overall, there was no main effect between any variant genotype, haplotype or diplotype and breast cancer risk. Heavy smoking (>31 pack-year) significantly increased breast cancer risk for women with the codon 84 variant T-allele [odds ratio, OR = 3.0, 95% confidence interval (95% CI) = 1.4-6.2]. An inverse association between fruits and vegetables consumption and breast cancer risk was observed among women with the wild-type genotype for codon 84 (OR = 0.8, 95% CI = 0.6-0.9 for > or =35 servings of fruits and vegetables per week and CC genotype versus those with <35 servings per week and CC genotype). The association between fruits and vegetables consumption and reduced breast cancer risk was apparent among women with at least one variant allele for codon 143 (OR = 0.6, 95% CI = 0.5-0.9 for > or =35 servings of fruits and vegetables per week and AG or GG genotype versus those with <35 servings per week and AA genotype). Similar patterns were observed for dietary alpha-carotene and supplemental beta-carotene, but not for supplemental vitamins C and E. These data suggest that polymorphisms in MGMT may modulate the inverse association previously observed between fruits and vegetables consumption, dietary antioxidants and breast cancer risk, and support the importance of fruits and vegetables on breast cancer risk reduction.
O(6)-甲基鸟嘌呤DNA甲基转移酶（MGMT）是DNA直接修复（DRR）途径中已知的唯一参与细胞抵御烷化剂的关键基因。已鉴定出编码非保守氨基酸替代的三种单核苷酸多态性（SNP）[C250T（Leu84Phe）、A427G（Ile143Val）和A533G（Lys178Arg）]。为了研究DRR途径在乳腺癌风险中的重要性以及与吸烟和膳食抗氧化剂的潜在相互作用，我们使用长岛乳腺癌研究项目的生物样本对这些变异进行了基因分型。基因分型通过荧光偏振高通量检测进行，包括1067例病例和1110例对照。总体而言，任何变异基因型、单倍型或双倍型与乳腺癌风险之间均无主要影响。重度吸烟（>31包年）显著增加了携带密码子84变异T等位基因女性的乳腺癌风险[比值比，OR = 3.0，95%置信区间（95%CI） = 1.4 - 6.2]。在密码子84野生型基因型的女性中观察到水果和蔬菜摄入量与乳腺癌风险之间呈负相关（每周食用≥35份水果和蔬菜且为CC基因型的女性与每周食用<35份水果和蔬菜且为CC基因型的女性相比，OR = 0.8，95%CI = 0.6 - 0.9）。在密码子143至少有一个变异等位基因的女性中，水果和蔬菜摄入量与降低乳腺癌风险之间的关联明显（每周食用≥35份水果和蔬菜且为AG或GG基因型的女性与每周食用<35份水果和蔬菜且为AA基因型的女性相比，OR = 0.6，95%CI = 0.5 - 0.9）。膳食α-胡萝卜素和补充β-胡萝卜素也观察到类似模式，但补充维生素C和E则未观察到。这些数据表明，MGMT基因多态性可能调节先前观察到的水果和蔬菜摄入量、膳食抗氧化剂与乳腺癌风险之间的负相关，并支持水果和蔬菜对降低乳腺癌风险的重要性。
