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The correlation between FHIT, P53 and MMR genes in human papillomavirus-associated cervical carcinoma.

BACKGROUND AND AIM
High risk human papillomavirus (HR-HPV) types have been closely associated with cervical carcinoma. However, other genetic events are likely to be required, in addition to HPV infection, for the development of cervical cancer. We investigated 20 human cervical carcinomas and 15 normal cervical tissues for the correlation between aberrant expression of the FHIT, p53 and MMR genes and their prognostic impact.


METHODS AND RESULTS
The expression of p53, FHIT and MMR genes (hMSH2, hMLH1,GTBP/hMSH6,hPMS2, hPMS1) was assessed in relation to HPV infection by immunohistochemistry and PCR. HPV-16 and 18 DNA were detected in 95% and 25%, HPV m-RNA in 90% and 10% of cases; respectively. Homozygous deletion (HZD) and reduced FHIT protein was detected in 40% and 65% of cases, respectively; 25% of which showed abnormal gene transcripts. Reduced MMR gene expression was found in 19 cases. hMSH2 and hMLH1 showed the highest frequency (80% and 70%, respectively). p53 overexpression was present in 50% of cases with a single mutation in exon 7. There was a significant relation between FHIT aberrations, HPV-16 RNA, reduced hMLH-1 and hMSH- 2 expression; between reduced expression of hMSH-2 and p53 overexpression, GTPB-6, as well as between GTPB-6 and hMLH-1. Aberrant expression of p53, FHIT, hMLH1and GTPB-6 was significantly associated with recurrence.


CONCLUSIONS
Aberrations involving MMR genes, FHIT and p53 are frequent in HPV-associated cervical carcinoma with a significant correlation between them. However, only the FHIT, p53, hMLH1 and GTPB6 aberrations could be used as predictors of tumor recurrences.