Cigarette smoking is a risk factor for
colorectal cancer. Putative colorectal procarcinogens in tobacco
smoke include
polycyclic aromatic hydrocarbons and heterocyclic aromatic
amines that are known substrates of
glutathione S-
transferases (
GSTs). This study examined the influence of functional GST gene polymorphisms on the smoking-
colorectal cancer association in a population known to be minimally exposed to dietary sources of these procarcinogens. Incident cases of
colorectal cancer (n = 480) and matched controls (n = 1167) were selected from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 men and women who have been followed since 1993. We determined the deletion polymorphisms of GSTM1 and GSTT1 and the functional polymorphism at
codon 105 of GSTP1 for each subject. A three level composite GST index was used to examine if GST profile affected a smoker's risk of developing
colorectal cancer. While there was no statistically significant association between cigarette smoking and
colorectal cancer risk among subjects absent of any at-risk GST genotypes, smokers possessing two to three at-risk GST genotypes exhibited a statistically significant increased risk of
colorectal cancer compared with non-smokers (P = 0.0002). In this latter stratum, heavy smokers exhibited a >5-fold increased risk relative to never-smokers (odds ratio, 5.43; 95% confidence interval, 2.22-13.23). Subjects with one at-risk GST genotype displayed a statistically significant but weaker association with smoking. These findings suggest that GST gene polymorphisms influence interindividual susceptibility to smoking-associated
colorectal cancer. Our data indicate an important role for GST
enzymes in the detoxification of colorectal
carcinogens in tobacco
smoke.