Human papillomavirus, Epstein‐Barr virus, and methylation status of p16^ink4a in penile cancer

Abstract

Little is known about penile carcinogenesis. The aim of this study was to evaluate the prevalence of HPV and EBV, and the methylation status of p16 in penile cancer samples, and to contribute to the understanding of the mechanisms responsible for penile cancer development. HPV DNA was detected in 63.6% of 122 cases, with HPV16 being the most prevalent type. EBV DNA was detected in 47.7%, with EBV-1 being the most prevalent type. HPV/EBV co-infections were found in 27.3% of the cases. Hypermethylation in p16 was detected in 64.5% of 110 tested cases. An association between the absence of HPV absence and p16 hypermethylation was also found. Death and/or progressive disease was associated with grade (P = 0.001), T stage (P < 0.0001), and N stage (P < 0.0001). In the multivariable model, grade and N stage were independent risk factors for disease-free survival (P = 0.008 and P < 0.001, respectively). Patients without viral infection had a median age significantly lower than that of the HPV-infected patients. We suggest at least two pathways for penile carcinogenesis, one HPV-independent linked to epigenetic events, probably via p16 inactivation; and another, dependent on HPV infection.

Prognostic Significance of HPV and p16 Status in Men Diagnosed with Penile Cancer: A Systematic Review and Meta-analysis

“…20, 21, 31, 33, 38-40, 43) used IHC. The remaining two studies used methylation specific PCR (29) and nested methylation specific PCR (42). Description of the definition of p16 positivity (overexpression) applied in the studies and number of evaluators of the p16 test are presented in Table 1. A total of 1,107 men with penile cancer were tested for HPV DNA of which 437 and 670 were HPV-positive and -negative, respectively.…”

“…Three studies (32,41,42) only examined DFS according to HPV status. A study by Afonso and colleagues (42) included 112 men with penile cancer who were followed for a median of 20 months (range 0-149 months). In a univariate analysis, they found that DFS was not significantly correlated with the presence of HPV (P ¼ 0.552).…”

“…Disease-free survival. Four studies (29,38,39,42) reported DFS according to p16 status. Tang and colleagues (39) detected p16 overexpression in 59 (49.6%) of 119 men with penile cancer.…”

Presence of HPV with overexpression of p16INK4a protein and EBV infection in penile cancer—A series of cases from Brazil Amazon

“…Epstein-Barr virus (EBV) is another agent associated with PC [17,18]. Inappropriate expression of its latent genes (Latent Membrane Protein) LMP-1, LMP-2A e LMP-2B, involved in cell persistence, may contribute to the development of tumors [19].…”

“…In HPV-associated cancer, the presence of EBV may also act as a viral cofactor [21]. Several studies have shown the presence of EBV and co-infection with HPV in PC but a relationship between PC and EBV is yet to be established [17,18].…”