Chacko Priya, Joseph Thomas, Mathew Beela Sarah, Rajan Balakrishnan, Pillai M Radhakrishna
Division of Molecular Medicine, Drug Development and Chemoinformatics, Regional Cancer Centre, Thiruvananthapuram 695011, Kerala, India.
Mutat Res. 2005 Mar 7;581(1-2):153-63. doi: 10.1016/j.mrgentox.2004.11.018. Epub 2005 Jan 18.
Metabolic activation and inactivation of potential genotoxic agents occur by Phase I and Phase II enzymes in multiple interactions. An expanding body of literature demonstrates that ethnic differences in breast cancer incidence may be partly caused by host genetic factors particularly genetic polymorphisms of these carcinogen-metabolizing enzymes. The present case-control study aimed at identification of such low penetrance breast cancer susceptibility genes in 224 Indian women and to investigate the potential effects of their polymorphisms on sporadic breast cancer risk. The main objective of the study was to evaluate the effects of genetic polymorphisms of the xenobiotic metabolizing genes CYP1A1, GSTM1 and GSTT1 on breast cancer risk by PCR-RFLP and DNA sequencing. Our results showed a significant association between CYP1A1 m1, m2 polymorphisms and breast cancer risk; however there was a lack of association between GSTM1 null deletion and breast cancer. The associations of CYP1A1, GSTM1 and GSTT1 genotypes with breast cancer risk were more pronounced among the pre-menopausal patients. Combined genotype analysis revealed the CYP1A1 m2 ValVal-GSTM1 homozygous null deletion genotype combinations to be associated with the highest risk of breast cancer (OR=10.3, 95% CI=1.2-86.1). Correlations with clinicopathological factors and treatment outcome were also analyzed for predicting disease free survival by univariate and multivariate analysis. Significant differences in disease free survival between the wild and polymorphic genotypes were observed only for CYP1A1 m2, GSTT1 genotypes. Our results based on the analysis of functionally relevant polymorphisms in these low penetrance genes may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer. Such genotype analysis resulting in a high-risk profile holds considerable promise for individualizing screening and therapeutic intervention in breast cancer. Hence, the present study may provide strong supportive evidence for genetic interactions in the etiology of breast cancer.
潜在的遗传毒性剂的代谢激活和失活通过I相和II相酶在多种相互作用中发生。越来越多的文献表明，乳腺癌发病率的种族差异可能部分是由宿主遗传因素引起的，特别是这些致癌物代谢酶的基因多态性。本病例对照研究旨在在224名印度女性中鉴定此类低外显率乳腺癌易感基因，并研究其多态性对散发性乳腺癌风险的潜在影响。该研究的主要目的是通过聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）和DNA测序评估外源性代谢基因CYP1A1、谷胱甘肽S-转移酶M1（GSTM1）和谷胱甘肽S-转移酶T1（GSTT1）的基因多态性对乳腺癌风险的影响。我们的结果显示CYP1A1 m1、m2多态性与乳腺癌风险之间存在显著关联；然而，GSTM1无效缺失与乳腺癌之间缺乏关联。CYP1A1、GSTM1和GSTT1基因型与乳腺癌风险的关联在绝经前患者中更为明显。联合基因型分析显示，CYP1A1 m2 ValVal-GSTM1纯合无效缺失基因型组合与最高的乳腺癌风险相关（比值比=10.3，95%可信区间=1.2-86.1）。还通过单因素和多因素分析分析了与临床病理因素和治疗结果的相关性，以预测无病生存期。仅在CYP1A1 m2、GSTT1基因型中观察到野生型和多态性基因型之间无病生存期的显著差异。我们基于对这些低外显率基因中功能相关多态性的分析结果，可能提供一个更好的模型，该模型将对个体对乳腺癌的易感性产生累加效应。这种导致高风险特征的基因型分析在乳腺癌个体化筛查和治疗干预方面具有很大的前景。因此，本研究可能为乳腺癌病因学中的基因相互作用提供有力的支持证据。
