Background: Glutathione S-transferases (GST) detoxify a broad range of carcinogenic metabolites and lack of GSTM1 and GSTT1 activity due to gene deletions are prevalent. The associations of GSTM1 and GSTT1 polymorphisms with endometrial cancer risk have been inconsistent.
Methods: We investigated gene dosage effects of GSTM1 and GSTT1 copy number in 441 endometrial cancer cases and 1,237 matched controls selected from the Nurses' Health Study and Women's Health Study, as well as gene-environment interactions.
Results: Carriers of at least 2 GSTT1 genes had an increased risk of endometrial cancer (OR = 1.51, 95% CI = 1.04-2.19; P(trend) = 0.04) compared with women who were GSTT1 null. GSTM1 was not associated with endometrial cancer risk (OR(2/3 vs. 0 copies) = 0.82, 95% CI = 0.52-1.27; P(trend) = 0.41). We did not observe effect modification of either the GSTM1 or GSTT1 association with cancer risk by smoking status, postmenopausal hormone use, or body mass index.
Conclusions: Our results suggested GSTM1 copy number does not influence endometrial cancer risk, whereas higher GSTT1 copy number may be associated with increased risk. Our findings supported that GSTT1 differs in its substrate specificity from GSTM1 and may generate intermediates more genotoxic to endometrial cells than the parent chemical. Future studies are needed to clarify this relationship.
Impact: We hypothesized risk associated with GST enzymes may differ depending on environmental and/or occupational exposures. Our assessment of gene-environment interactions suggested GSTM1 and GSTT1 are not involved in the in vivo human metabolism of estrogen and its metabolites.