Naushad Shaik Mohammad, Hussain Tajamul, Al-Attas Omar S, Prayaga Aruna, Digumarti Raghunadha Rao, Gottumukkala Suryanarayana Raju, Kutala Vijay Kumar
School of Chemical & Biotechnology, SASTRA University, Thanjavur, 613401, India.
Mol Cell Biochem. 2014 Jul;392(1-2):273-80. doi: 10.1007/s11010-014-2037-z. Epub 2014 Mar 28.
Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR-RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with "Luminal A" breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p < 0.05), Ras-association (RalGDS/AF-6) domain family member 1 (RASSF1A) (r = 0.31, p < 0.001), and breast cancer type 1 susceptibility protein (r = 0.19, p < 0.05); and inverse association with methylation of BNIP3 (r = -0.48, p < 0.0001). To conclude based on these results, obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.
肥胖、外源性代谢途径的基因多态性、肿瘤抑制基因的高甲基化以及促凋亡基因的低甲基化是已知的乳腺癌独立危险因素。本研究的目的是评估这些环境、遗传和表观遗传危险因素对乳腺癌易感性的综合影响。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和多重PCR对外源性代谢途径的六个变体进行基因分析。采用甲基化特异性PCR对四个基因位点进行表观遗传分析。多因素降维分析显示，体重指数（BMI）与儿茶酚-O-甲基转移酶H108L变体单独或与细胞色素P450（CYP）1A1m1变体联合存在显著相互作用。与其他表型和健康对照相比，具有“Luminal A”乳腺癌表型的女性BMI更高。BMI与肿瘤分级之间无关联。绝经后肥胖女性的谷胱甘肽水平较低。BMI与细胞外超氧化物歧化酶甲基化呈正相关（r = 0.21，p < 0.05）、与Ras关联（RalGDS/AF-6）结构域家族成员1（RASSF1A）甲基化呈正相关（r = 0.31，p < 0.001）、与乳腺癌1型易感蛋白甲基化呈正相关（r = 0.19，p < 0.05）；与BNIP3甲基化呈负相关（r = -0.48，p < 0.0001）。基于这些结果得出结论，肥胖通过两种可能的机制增加乳腺癌易感性：（i）通过与外源性基因多态性相互作用诱导氧化DNA损伤增加；（ii）通过改变几种肿瘤抑制基因的甲基化组。
