Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 EM and glutathione s-transferase GSTM1 null genotypes and cigarette smoking.

Ap Warwick,Cwe Redman,Aa Fryer,Rc Strange,J Gilford,J Alldersea,Pw Jones

doi:10.1038/bjc.1994.378

Abstract

The factors that determine progression of cervical intraepithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette smoking is an independent risk factor for cervical neoplasia, suggesting that polymorphism at detoxicating enzyme loci such as cytochrome P450 CYP2D6 and glutathione S-transferase GSTM1 may determine susceptibility 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 histology suffering menorrhagia. Comparison of the frequency distributions 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 differences between the menorrhagia and SCC groups. Frequency distributions in the menorrhagia group, however, were significantly different (P < 0.04) from those in the low- and high-grade CIN groups. Thus, the proportion of EM was significantly larger (P < 0.03) and of HET generally lower. We found that the frequency of GSTM1 null in the menorrhagia and 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 over mutually exclusive categories. These showed no significant differences 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-grade CIN groups. This study was identified, for the first time, an inherited characteristic in women with high-grade CIN who appear to be at reduced risk of SCC. Thus, women with CYP2D6 EM who smoke have increased susceptibility to high-grade CIN but are less likely to progress to SCC, possibly because they effectively detoxify an unidentified chemical involved in mediating disease progression.

Highlights

Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 extensive metaboliser (EM) and glutathione S-transferase GSTM1 null genotypes and cigarette smoking
women with CYP2D6 EM who smoke have increased susceptibility to high-grade cervical intraepithelial neoplasia (CIN) but are less likelv to progress to squamous cell carcinoma (SCC). possibly because they effectively detoxify an unidentified chemical involved in mediating disease progression
Data showing that metastatic progression of primary cervical cancers may be accompanied by GC-*TA transversions in p53 suggest a role for carcinogens such as benzpyrene and aflatoxin B (Crook et al, 1992), mutations in the hotspot regions of this gene appear to be infrequent in cervical carcinomas (Paquette et al.. 1993: Busby-Earle et al.. 1994)

Summary

Introduction

Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 EM and glutathione S-transferase GSTM1 null genotypes and cigarette smoking. Summan The factors that determine progression of cervical intraepithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Interactive effects of enzyme genotypes with cigarette smoking were studied bv comparing the multinomial frequency distributions of CYP2D6 EM GSTMI null smoking over mutuallv exclusive categories. These showed no significant differences between the menorrhagia group and SCC or low-grade CIN groups. Women with CYP2D6 EM who smoke have increased susceptibility to high-grade CIN but are less likelv to progress to SCC. Data showing that metastatic progression of primary cervical cancers may be accompanied by GC-*TA transversions in p53 suggest a role for carcinogens such as benzpyrene and aflatoxin B (Crook et al, 1992), mutations in the hotspot regions of this gene appear to be infrequent in cervical carcinomas (Paquette et al.. 1993: Busby-Earle et al.. 1994)

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