Polymorphism in cytochrome P450 2A6 and glutathione S-transferase P1 modifies head and neck cancer risk and treatment outcome

Abstract

A case control study was carried out to investigate the association of functionally important polymorphism in cytochrome P450 2A6 ( CYP2A6) and glutathione S-transferase P1 ( GSTP1) genes with head and neck squamous cell carcinoma (HNSCC) and treatment response in cases receiving a combination of chemo-radiotherapy. The study group consisted of 350 males suffering from HNSCC and an equal number of male controls. Multivariate logistic regression analysis revealed statistically significant decrease in risk to HNSCC in cases with variant genotypes ( CYP2A6*1B and CYP2A6*4C) of CYP2A6 (OR: 0.78; 95% CI: 0.43–1.22; P = 0.04) or GSTP1 (OR: 0.71; 95% CI: 0.51–1.00; P = 0.05). The risk associated with these variant genotypes was found to be further decreased in cases carrying a combination of variant genotypes of CYP2A6 and GSTP1 (OR: 0.40; 95% CI: 0.25–0.65; P = 0.00). A similar decrease in risk was observed in cases with variant genotypes of CYP2A6 (OR: 0.59; 95% CI: 0.40–0.86; P = 0.00) or GSTP1 (OR: 0.62; 95% CI: 0.42–0.91; P = 0.01) and who were regular tobacco users (cigarette smokers or tobacco chewers). Interestingly, only 27% of the cases carrying the variant forms of CYP2A6 ( *1A/ *4C + *1B/ *4C + *4C/ *4C) responded to the treatment for HNSCC when compared to those with wild-type genotype (69%). However with GSTP1, cases with homozygous mutant genotype ( Val/ Val) showed a superior treatment response (75%) when compared to cases with wild-type genotype (25%). Further, cases carrying a combination of variant genotype of CYP2A6 and wild-type genotype of GSTP1 exhibited a very poor treatment response demonstrating that polymorphisms in CYP2A6 and GSTP1 not only modified the risk to HNSCC but also played a major role in determining the chemotherapeutic response.