Gene environment interaction between ERCC5 and tobacco in oral premalignancies

Objective: to assess the role of genetic variation at ERCC5 during the early phases of oral carcinogenesis. ERCC5 is found on chromosome 13 (13q33) and it is involved in the regulation of DNA repair. Methods: 106 individuals with confirmed oral premalignancies (OPs) and 212 healthy controls were selected to participate in a nested case-control within the Health Professionals Follow Up Study (HPFS), a group of 55,000+ health professionals who are followed up regularly since 1986. Cases and controls provided information on smoking, alcohol use, diet, and demographics. They also volunteered to provide blood. After DNA extraction, PCR based genotyping methods were used to characterize among others the genotype rs751402 (exon 1, C/T, with 42% described heterozygosity). Results were analyzed using logistic regression in Stata 9.0. Results: Bivariate and multivariate statistics confirmed that tobacco and alcohol use increase the risk of OP where fruit consumption was associated with reduced risks. With regard to smokeless tobacco use, the odds ratio (OR) was 3.5, with a 95% confidence interval (C.I) of 1.4-8.5 (p<0.05). The risk of premalignancy among homozygotes for ERCC5 rs751402 was increased by 89% (95% C.I: 1.1-3.2) as compared with individuals who did not harbor the genotype. However multivariate stratified analysis revealed that ERCC5 rs751402-positive individuals had a 26-fold increase in their risk if the used tobacco (95% C.I: 1.03-669.1). The statistical interaction was significant (OR=5.1, 95% C.I: 1.9- 13.8).

Conclusions: We documented a strong gene environment interaction between ERCC5 and smokeless tobacco use. This is the first report to describe an interaction between the genetics of DNA repair and the use of smokeless tobacco in oral carcinogenesis. While biologically plausible, more studies are needed to confirm the finding which has a direct clinical implication in the early identification of susceptible individuals for oral cancer.

Research funded by NIDCR DE015593.