The development of HPV-related cervical cancer: The influence of NQO1 and p53 polymorphic variation


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Qasem Abdallah, Milene Volpato, Beryl Cronin, Sandie Martin, Roger Phillips

Institute of Cancer Therapeutics, University of Bradford, Bradford, UK

Abstract

NAD(P)H:Quinone oxidoreductase 1 (NQO1) has multiple functions in cells including the stabilisation of p53 via a mdm2 independent route and the partial abrogation of HPV mediated p53 degradation. Two polymorphic variants of NQO1 (NQO1*2 and *3) cause loss of NQO1 activity raising the possibility that individuals harboring these variants may have improper p53 function and increased susceptibility to HPV mediated cervical cancers. The aim of this study was to survey NQO1 genotypes (and the p53 polymorphism at codon 72) in a population of patients with pre-neoplastic and cancerous lesions of the cervix.

Genomic DNA was extracted from histological blocks of cervical cancer (n=90) and pre-cancerous CIN lesions (n=293) and NQO1 polymorphic status determined by real-time PCR. No significant difference exists between the distribution of NQO1*2 and p53*72 in either patient group or the distribution reported in healthy individuals. In contrast, a significant increase in the incidence of the mutated form of the NQO1*3 polymorphism with a risk ratio of 2.53 (95% conf. interval= 3.52, Pr>Chi2= 0.0000) was observed in patient with cervical cancer. Additionally, no relationship was established between the NQO1 polymorphic variants and the CIN grade of the patients.

In conclusion, higher incidence of the NQO1*3 polymorphism was observed within the cancerous group compared to both healthy and pre-cancerous groups. Whilst the mechanistic basis for this observation is not known, this study suggests that individuals which harbour NQO1*3 maybe at greater risk of progressing from CIN to malignant cervical cancer.

NAD(P)H:Quinone oxidoreductase 1 (NQO1) has multiple functions in cells including the stabilisation of p53 via a mdm2 independent route and the partial abrogation of HPV mediated p53 degradation. Two polymorphic variants of NQO1 (NQO1*2 and *3) cause loss of NQO1 activity raising the possibility that individuals harboring these variants may have improper p53 function and increased susceptibility to HPV mediated cervical cancers. The aim of this study was to survey NQO1 genotypes (and the p53 polymorphism at codon 72) in a population of patients with pre-neoplastic and cancerous lesions of the cervix.

Genomic DNA was extracted from histological blocks of cervical cancer (n=90) and pre-cancerous CIN lesions (n=293) and NQO1 polymorphic status determined by real-time PCR. No significant difference exists between the distribution of NQO1*2 and p53*72 in either patient group or the distribution reported in healthy individuals. In contrast, a significant increase in the incidence of the mutated form of the NQO1*3 polymorphism with a risk ratio of 2.53 (95% conf. interval= 3.52, Pr>Chi2= 0.0000) was observed in patient with cervical cancer. Additionally, no relationship was established between the NQO1 polymorphic variants and the CIN grade of the patients.

In conclusion, higher incidence of the NQO1*3 polymorphism was observed within the cancerous group compared to both healthy and pre-cancerous groups. Whilst the mechanistic basis for this observation is not known, this study suggests that individuals which harbour NQO1*3 maybe at greater risk of progressing from CIN to malignant cervical cancer.