Carcinogenesis Advance Access published online on February 16, 2007
Carcinogenesis, doi:10.1093/carcin/bgm038
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Susceptibility to Oral Cancer by Genetic Polymorphisms at CYP1A1, GSTM1 and GSTT1 Loci among Indians: Tobacco Exposure as a Risk Modulator
1 Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai-410 208, India
2 BTIS Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai-410 208, India
3 Zoology Department, University of Pune, Ganesh Khind, Pune-411007, India
* To whom correspondence should be addressed: Dr.Manoj B. Mahimkar, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai-410208, India. Phone No: 91-22-2740 5000, Ext 5049, Email address: mmahimkar{at}actrec.gov.in Fax No: 91-22- 27405085 / 5058
Oral cancer is the leading cancer type among Southeast Asian men and is causally associated with the use of tobacco. Genetic polymorphisms in xenobiotic metabolizing enzymes modify the effect of environmental exposures, thereby playing a significant role in gene-environment interactions and hence contribute to the high degree of variance in individual susceptibility to cancer risk. This study investigates the role of polymorphisms at CYP1A1, GSTM1 and GSTT1 to oral squamous cell carcinoma in a case-control study involving 155 patients with precancerous lesions, 458 cancer patients and 729 age and habit matched controls. Genotypes at these loci were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism performed on genomic DNA extracted from peripheral blood lymphocytes. Risk to oral cancer was estimated among different tobacco exposure groups and doses using logistic regression analysis. GSTM1 null genotype conferred 1.29 fold-increased risk (95% CI, 1.04-1.65) to oral squamous cell carcinoma (OSCC). GSTT1 null genotype however, conferred 0.57 times reduced risk to OSCC (95% CI, 0.39-0.83), specifically among tobacco chewers (OR 0.27, 95% CI, 0.14-0.53). This risk was further reduced to 0.13 times (95% CI, 0.04-0.46) with increase in lifetime exposure to tobacco. We also investigated risk conferred by these genotypes at two different intra-oral sites, buccal mucosa and tongue. We found increased susceptibility to buccal mucosa cancer among individuals carrying these genetic markers. These results support the finding that GSTM1 null genotype is a risk factor to OSCC among Indian tobacco habitués; GSTT1 null genotype however, emerged as a protective factor.
Key Words: Oral cancer • Genetic polymorphism • gene- environment interaction • CYP1A1 MspI • GSTM1 • GSTT1 • smokeless tobacco
Received October 18, 2006; revised December 18, 2006; revised February 8, 2007; accepted February 11, 2007.
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