Epigenetic Events

Methylation of CpG-rich islands in or near the promoter region of genes has been associated with transcriptional inactivation of tumor-suppressor and tumor-related genes in human cancers. So far, a few studies have searched for DNA methylation of cellular genes in penile carcinoma. Yanagawa et al.26,52 revealed frequencies of methylation as follows: 27% for DAPK, 88% for FHIT, 19% for MGMT, 23% for RAR-beta, 12% for ras association domain family 1A (RASSF1A), and 42% for RUNX3. The high frequency of methylation of the FHIT gene promoter is noteworthy. FHIT gene promoter hypermethylation was associated with absence of FHIT expression.52 FHIT has a role in the regulation of apoptosis and the cell cycle, which may be lost upon promoter hypermethylation. In general, methyla-tion of the above markers was observed more frequently in HPV-negative than in

HPV-positive patients, though data should be interpreted with care as only 3 HPV-positive patients were included in the study.26 Another study reports methylation status in the promoter region of thrombospondin-1 (TSP-1) and RASSF1A in 46% and 42% of the tumors, respectively. The epigenetic inactivation of TSP-1 and RASSF1A genes was found associated with pathological variables (i.e., unfavorable histological grade, vascular invasion, and shorter overall survival for TSP-1; and T1 tumors for RASF1A). Both methylation markers seemed to be of prognostic significance in penile cancer, yet with opposite roles, i.e., TSP-1 promoter methylation was associated with shorter 5-year disease-free survival and overall survival, while RASSF1A hypermethylation seemed to be associated with a more prolonged-disease free survival.36

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