HPV HAS LEFT THE BUILDING - THE ABSENCE OF DETECTABLE HPV DNAAND THE PRESENCE OF R ALLELE/S FOR THE P72R POLYMORPHISM IN THE TP53 GENE MAY CALL FOR MORE AGGRESSIVE THERAPEUTIC APPROACH IN HPV-ASSOCIATED TUMOURS

摘要

HPV infection is a major pathogenetic factor in cervical carcinoma as well as in many of the squamous cancers of head and neck and other epithelial cancers. Persistence of HPV DNA detectable by routine methods is considered to be a risk factorfor advanced CIN and, in patients treated by surgery or non-surgical treatment modalities (radiotherapy, chemotherapy), HPV persistence is believed to be associated with increased risk for local recurrence. In terms of survival, however, it has been repeatedly proven that patients with cervical cancer and other HPV-associated cancers with detectable HPVDNA tend to have better outcomes than patients with HPV-negative tumours. The P72R polymorphism in the human TP 5 3 gene has been contemplated as an independentphenotype modifier in cancers, especially the R allele which has been shown to confer higher pro-apoptotic properties to the resultant p53 protein. It has been demonstrated, however, that RR homozygotes were much more common in study groups with HPV-associated tumours than the other two genotypes and that the P allele in P/R heterozygotes was preferentially lost while the R allele was preferentially retained and mutated. It is possible that HPV-dependent carcinogenesis strictly relies on the presence ofHPV and the expression of the E6 and E7 oncoproteins only in the initial phases of transformation of infected cells (e.g. CIN). It may be associated with activation of latent HPV that would create a background of decreased control over the integrity ofthe genome of the host cell. The process can develop further by mechanisms independent of the presence of HPV and if the virus clears at some later point, that would not halt the already ongoing neoplastic transformation. Absence of HPV DN A in cervicaltumours, whether before or after treatment, is not a reason to decrease vigilant monitoring and rule out the need for further treatment, as it may be quite possible that the TP 53 gene of the infected cells has already been modified in the course of cancer progression by HPV-independent mutagenesis. Cervical tumours that are HPV-negative ought to alert attending oncologists for the possibility for increased growth potential and invasiveness of the tumour so as to contemplate more aggressive anticancer therapies, especially in carriers of the R allele of the P53R polymorphism.