Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility.

Abstract

The mu (GSTM1 and theta (GSTT1) members of the glutathione S-transferase multigene family are candidate cancer susceptibility genes because of their ability to regulate the conjugation of carcinogenic compounds to excretable hydrophilic metabolites. Deletion variants that are associated with a lack of enzyme function exist at both these loci. Individuals who are carriers of homozygous deletions in the GSTM1 of GSTT1 genes may have an impaired ability to metabolically eliminate carcinogenic compounds and may therefore be at increased cancer risk. Molecular epidemiological studies have provided three pieces of information about the relationship of GSTM1 and GSTT1 with cancer susceptibility. First, the frequencies of homozygous GSTM1 and GSTT1 deletion carriers is very high (i.e., 20-50%) in most populations studied to date. Second, GSTM1 and, possibly, GSTT1 may be involved in the etiology of cancer at more than one site. Third, the risk conferred to individuals who carry homozygous deletions in GSTM1 and GSTT1 appears to be small in magnitude. (e.g., odds ration of < 2). However, the magnitude of risk is larger (e.g., odds ratio of 3-5) when interactions of GSTM1 of GSTT1 with other factors (e.g., cigarette smoking) are considered. These findings have implications for studies of GSTM1 and GSTT1 in cancer susceptibility and for future applications of these biomarkers in cancer prevention of control strategies. First, molecular epidemiological studies should consider both the common frequency of deletion genotypes and the relatively low cancer risk these deletion genotypes may impart. For example, the common frequency of deletion variants may improve statistical power in some molecular epidemiological studies, but large samples may still be required to detect relatively small effect sizes or important interaction effects. Second, the fact that deletion genotypes are common implies that the proportion of cancer attributable to these variants may be large in the general population. However, these genotypes may be less suited for individual cancer risk assessment because of their relatively small contribution to the absolute risk of cancer.