Mecanismos epigenéticos e variantes genômicas associados a infecção por HPV no câncer de pênis

Abstract

Penile cancer (CPE) is a rare tumor, which affects approximately 2% of the male population. The incidence increase of the disease is mainly related to low socioeconomic conditions. Human papillomavirus (HPV) infection is related to approximately 50% of penile SCC cases. Multiple risk factors are related to the disease and the lack of information associated with social stigma, late diagnosis and limited therapy limits the chances of cure. The objective of this work is to evaluate epidemiological and prognostic aspects of CPE, as well as identify the relationship between high-risk HPV (hrHPV) infection in 224 participants. We also describe the pattern of the global DNA methylation and hydroxymethylation marks, 5- methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), respectively, identify the methylation pattern of the differentially methylated region, H19DMR, and present preliminary data from an exome panel. We observed that the incidence of HPV was 53.2% for high-risk HPV and 22.32% for the p16INK4a marker. hrHPV was not related to systemic or lymph node metastasis and locoregional recurrence, nor did it influence the survival rate. Expression of the p16INK4a marker appears to be a factor for a positive stage and does not affect metastasis or tumor recurrence. Lymph node and systemic metastases and locoregional recurrence increase the risk of death. Our results indicate a significant increase in the 5mC mark in CPE, regardless of HPV infection. However, we reported a reduction in 5hmC for p16INK4a+ (P = 0.024). An increase in the 5mC/5hmC ratio (> 1) was observed in 94.2% of SCC, regardless of HPV infection. Despite the 5mC increase, this fact does not seem to affect the survival rate (HR = 1.06; 95% CI 0.33–3.38). We observed an average methylation of 32.2%±11.6% in H19DMR of CPE, with no association between the markers p16INK4a+ (p = 0.59) and hrHPV+ (p = 0.338) with the methylation level. We observed a positive brightness between infiltration of polymorphonuclear cells and hypomethylation in H19DMR (p = 0.035). Preliminary analysis of an exome panel, we observed previously undescribed genes with high mutational frequency (MUC5B, MUC16, OBSCN, MUC12, CMYA5, SVEP1, LEMAS5, SPTA1 and FSIP2). The molecular characterization of CPE encourages and favors new studies that can suggest specific treatment strategies, such as hypomethylating agents for epigenetic targeted therapies, establish new targets with druggable gene profiles and encourage the search for less invasive therapies.