P-A5 Genetic and epigenetic changes as biomarkers of progression in HPV-related cancers

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Abstract

Persistent infections of high-risk a human papilloma viruses (HR-HPVs) are often associated with progression to mucosal cancers in ano-genital as well as oropharyngeal areas. Also for cervical cancers, for which screening programs are available, it is difficult to identify the lesions at high risk of progression to invasive cancers. Molecular markers able to identify viral infections associated with progressing cervical neoplasia are strongly needed for cervical cancer screening and triage. In particular predictive biomarkers are needed for detecting lesions at high risk of recurrence/progression in order to implement appropriate treatment and for avoiding overtreatment of those at high probability of regression. In order to achieve such goal we have performed the expression profile analysis of p53-related genes in HPV16-positive genital carcinomas along with autologous non-tumor tissue, and identified significant differences in the expression levels of genes involved in regulation of apoptosis, cell cycle, proliferation and DNA repair pathways. In particular, BRCA1, CDKN2A (p16), CASP2 and TNFRSF10B genes were significantly up-regulated (p<0.05) in cancer lesions and appear to be good candidates for predictive biomarkers. More recently analysis of TERT-gene promoter are showing the high frequency of activating mutations (30.4% of penile cancers as well as 26.1% of cervical cancer) in lesions associated with less oncogenic HPV genotypes (ie, HPV53), and even in HPV-negative lesions. Validation of these candidate biomarkers is currently in progress on a larger number of cases, including different grades of HPV-related neoplastic lesion (CIN1-3 and invasive cervical cancer) in association with epigenetic markers (i.e. gene methylation and miRNA expression profiles). Such studies will contribute to the development of new tools for the identification of premalignant lesions at high risk of progression to invasive cervical carcinoma.

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