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Background  In order to elucidate a combination of genetic alterations that drive tobacco carcinogenesis we have explored a unique model system and analytical method for an unbiased qualitative and quantitative assessment of gene-gene and gene-environment interactions. The objective of this case control study was to assess genetic predisposition in a biologically enriched clinical model system of tobacco related cancers (TRC), occurring as Multiple Primary Neoplasms (MPN).    Methods  Genotyping of 21 candidate Single Nucleotide Polymorphisms (SNP) from major metabolic pathways was performed in a cohort of 151 MPN cases and 210 cancer-free controls. Statistical analysis using logistic regression and Multifactor Dimensionality Reduction (MDR) analysis was performed for studying higher order interactions among various SNPs and tobacco habit.    Results  Increased risk association was observed for patients with at least one TRC in the upper aero digestive tract (UADT) for variations in  SULT1A1  Arg 213 His,  mEH  Tyr 113 His,  hOGG1  Ser 326 Cys,  XRCC1  Arg 280 His and  BRCA2  Asn 372 His. Gene - environment interactions were assessed using MDR analysis. The overall best model by MDR was  tobacco habit / p53 (Arg/Arg)/ XRCC1 (Arg 399 His)/ mEH (Tyr 113 His) that had highest Cross Validation Consistency (8.3) and test accuracy (0.69). This model also showed significant association using logistic regression analysis.    Conclusion  This is the first Indian study on a multipathway based approach to study genetic susceptibility to cancer in tobacco associated MPN. This approach could assist in planning additional studies for comprehensive understanding of tobacco carcinogenesis.

Multiple Pathway-Based Genetic Variations Associated with Tobacco Related Multiple Primary Neoplasms