Sulfotransferase 1A1 haplotypes associated with oral squamous cell carcinoma susceptibility in male Taiwanese

We have previously demonstrated that betel quid containing safrole induced DNA adducts are highly associated with the development of oral squamous cell carcinoma (OSCC) in Taiwan. Sulfotransferase (SULT) is essential for the formation of these adducts. To elucidate the effects of SULT1A1 haplotypes on OSCC susceptibility, 160 male OSCC cases and 218 age- and sex-matched controls were screened for single-nucleotide polymorphisms within the coding region of SULT1A1 by sequencing. We found that 445C > T (His149Tyr) and 507C > T polymorphisms were significantly associated with increased risk of OSCC. Based on the genotype analysis, haplotypes were constructed for 445C > T (His149Tyr), 507C > T, 600G > C and 638G > A (Arg213His) using GENECOUNTING software. After adjustment for age, cigarette smoking and betel quid chewing, we found that haplotype c containing 445C > T (His149Tyr), 507C > T or 600G > C but not 638G > A (Arg213His) variant was significantly associated with increased risk of OSCC (odds ratio, 3.24; 95% confidence interval, 1.57-6.68) when compared with the haplotype a (wild-type). We analyzed the activity in sulfonation of 2-naphthol and 1'-hydroxysafrole of recombinant His149Tyr (445C > T) variant, which led to 51 and 33% reduced activity, respectively; Arg213His (638G > A) variant led to 72 and 54% reduced activity, respectively, when compared with the wild-type. Taken together, haplotype analysis provides a novel evaluation of the SULT1A1 gene as a risk modifier on environmental carcinogen in OSCC and the association of SULT1A1 haplotypes with the risk of OSCC might be modified by betel quid chewing.