Multiple pathway-based genetic variations associated with tobacco related multiple primary neoplasms

• Published in: PloS one 2012-01, Vol.7 (1), p.e30013
• Main Authors: Kotnis, Ashwin, Namkung, Junghyun, Kannan, Sadhana, Jayakrupakar, Nallala, Park, Taesung, Sarin, Rajiv, Mulherkar, Rita
• Format: Article
• Language: English
• Subjects: Adult; Aged; Analysis; Biology; BRCA2 protein; Breast cancer; Cancer; Cancer research; Carcinogenesis; Carcinogens; Cell Transformation, Neoplastic - genetics; Demography; Digestive tract; Disease susceptibility; Environmental assessment; Female; Gastrointestinal tract; Genes; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic research; Genetic Variation; Genotype-environment interactions; Genotyping; Health risk assessment; Humans; Male; Medicine; Metabolic pathways; Middle Aged; Model accuracy; Models, Biological; Multifactor Dimensionality Reduction; Neoplasms; Neoplasms, Multiple Primary - genetics; Nicotiana - adverse effects; p53 Protein; Penetrance; Polymorphism; Polymorphism, Single Nucleotide - genetics; Qualitative analysis; Regression analysis; Signal Transduction - genetics; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Statistical analysis; Systematic review; Tobacco; Tumors; XRCC1 protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0030013

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). 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. Increased risk association was observed for patients with at least one TRC in the upper aero digestive tract (UADT) for variations in SULT1A1 Arg²¹³His, mEH Tyr¹¹³His, hOGG1 Ser³²⁶Cys, XRCC1 Arg²⁸⁰His and BRCA2 Asn³⁷²His. Gene-environment interactions were assessed using MDR analysis. The overall best model by MDR was tobacco habit/p53(Arg/Arg)/XRCC1(Arg³⁹⁹His)/mEH(Tyr¹¹³His) that had highest Cross Validation Consistency (8.3) and test accuracy (0.69). This model also showed significant association using logistic regression analysis. 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.