PROGRESSION OF CERVICAL INTRAEPITHELIAL NEOPLASIA TO CERVICAL-CANCER - INTERACTIONS OF CYTOCHROME-P450-CYP2D6-EM AND GLUTATHIONE-S-TRANSFERASE GSTM1 NULL GENOTYPES AND CIGARETTE-SMOKING

The factors that determine progression of cervical intraepithelial neo plasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette s moking is an independent risk factor for cervical neoplasia, suggestin g that polymorphism at detoxicating enzyme loci such as cytochrome P45 0 CYP2D6 and glutathione S-transferase GSTM1 may determine susceptibil ity to these cancers. We have studied the frequencies of genotypes at these loci in women suffering low-grade CIN, high-grade CIN and SCC. A non-cancer control group was provided by women with normal cervical h istology suffering menorrhagia. Comparison of the frequency distributi ons of the CYP2D6 PM, HET and EM genotypes (G-->A transition at intron 3/exon 4 and base pair deletion in exon 5) revealed no significant di fferences between the menorrhagia and SCC groups. Frequency distributi ons in the menorrhagia group, however, were significantly different (P <0.04) from those in the low- and high-grade CIN groups. Thus, the pr oportion of EM was significantly larger (P<0.03) and of HET generally lower. We found that the frequency of GSTM1 null in the menorrhagia an d case groups was not significantly different. Interactive effects of enzyme genotypes with cigarette smoking were studied by comparing the multinomial frequency distributions of CYP2D6 EM/GSTM1 null/smoking ov er mutually exclusive categories. These showed no significant differen ces between the menorrhagia group and SCC or low-grade CIN groups. The frequency distribution in high-grade CIN, however, was significantly different to that in the menorrhagia group and in both SCC and low-gra de CIN groups. This study has identified, for the first time, an inher ited characteristic in women with high-grade CIN who appear to be at r educed risk of SCC. Thus, women with CYP2D6 EM who smoke have increase d susceptibility to high-grade CIN but are less likely to progress to SCC, possibly because they effectively detoxify an unidentified chemic al involved in mediating disease progression.