THETA-CLASS GLUTATHIONE-S-TRANSFERASE GSTT1 GENOTYPES AND SUSCEPTIBILITY TO CERVICAL NEOPLASIA - INTERACTIONS WITH GSTM1, CYP2D6 AND SMOKING

The factors that determine progression of cervical intraepithelial neo plasia (GIN) to squamous cell carcinoma (SCC) are unknown. Cigarette s moking is a risk factor, suggesting polymorphism at loci that encode c arcinogen-metabolizing enzymes such as glutathione S-transferase (GSTT 1, GSTM1) and cytochrome P450 (CYP2D6) may determine susceptibility to these cancers. We have studied the frequency of the null genotype at the theta class GSTT1 locus in women with low-grade CIN, high-grade CI N and SCC. The control group comprised women with normal cervical path ology suffering menorrhagia. We found the frequency of GSTT1 null in t he control and case groups was not significantly different, though fre quency distributions of combinations of the genotype with smoking in m utually exclusive groups in the high-grade CIN group and the other cas e groups were significantly different. Interactive effects of GSTT1 nu ll with the GSTM1 null and CYP2D6 EM genotypes, and cigarette smoking were also studied by comparing the multinomial frequency distributions of these factors over mutually exclusive categories. These showed no significant differences between the controls and SCC or low-grade CIN. Frequency distributions in high-grade CIN, however, were significantl y different to the controls, and both SCC and low-grade CIN; frequency distributions of GSTT1 null with smoking and CYP2D6 EM, individually and in combination, were significantly different. However, inspection of our data does not indicate that GSTT1 null is a major factor mediat ing risk. Thus, comparison of chi(2) values for the differences betwee n frequency distributions in high-grade CIN and other groups shows tha t values for combinations of GSTT1 null with other factors are lower t han those for equivalent combinations with smoking and CYP2D6 EM. Inte restingly, the combination GSTT1 null/GSTM1 null did not appear to inf luence susceptibility to CIN or SCC.