title: Role of xenobiotic metabolizing gene polymorphisms in breast cancer susceptibility and treatment outcome.
abstract: 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.
authors.affiliation: Division of Molecular Medicine, Drug Development and Chemoinformatics, Regional Cancer Centre, Thiruvananthapuram 695011, Kerala, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Chacko
authors.forename: Thomas
authors.initials: T
authors.lastname: Joseph
authors.forename: Beela Sarah
authors.initials: BS
authors.lastname: Mathew
authors.forename: Balakrishnan
authors.initials: B
authors.lastname: Rajan
authors.forename: M Radhakrishna
authors.initials: MR
authors.lastname: Pillai
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D002273:Carcinogens / Q000378:metabolism; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D016019:Survival Analysis; D016896:Treatment Outcome; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; D015262:Xenobiotics; C413545:glutathione S-transferase T1