Polymorphisms and haplotypes of serine hydroxymethyl-transferase and risk of squamous cell carcinoma of the head and neck: A case-control analysis

Low dietary intake of fruits and vegetables, particularly folate deficiency, has been associated with the risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of the cytosolic serine hydroxymethyltransferase (SHMT1) gene involved in folate-dependent, one-carbon metabolism are associated with SCCHN risk. In a hospital-based, case-control study of 721 non-Hispanic white SCCHN patients and 1234 control subjects, frequency-matched by age and sex, three known SHMT1 polymorphisms (34761C > T, 34840C > G and 34859C > T) were genotyped. It was found that none of these three polymorphisms alone had a significant main effect on the risk of SCCHN. However, when the three polymorphisms were evaluated together by the number of the variant (risk) haplotype alleles (i.e. 34761 T, 34840G or 34859 T), the risk of SCCHN was significantly increased in a dose-response manner as the number of variant haplotype alleles increased compared to those with zero variant alleles [adjusted odd ratio (OR) = 1.39, 95% confidence interval (CI) = 1.14-1.70 for 1-3 variant alleles and OR = 1.46, 95% CI = 1.09-1.97 for 4-6 variant alleles; P_trend = 0.001]. In stratification analysis, this significant association was confined to younger men (≤ 64 years), ever smokers, ever drinkers and patients whose primary tumor site was in the pharynx or larynx. In conclusion, these three SHMT1 polymorphisms may play a joint role in the etiology of SCCHN in a non-Hispanic white population.