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HPV infection and 5mC/5hmC epigenetic markers in penile squamous cell carcinoma: new insights into prognostics.

ABSTRACT: Penile cancer is one of the most aggressive male tumors. Although it is preventable, the main etiologic causes are lifestyle behaviors and viral infection, such as human papillomavirus (HPV). Long-term epigenetic changes due to environmental factors change cell fate and promote carcinogenesis, being an important marker of prognosis. We evaluated epidemiological aspects of penile squamous cell carcinoma (SCC) and the prevalence of HPV infection using high-risk HPV (hrHPV) and p16INK4A expression of 224 participants. Global DNA methylation was evaluated through 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). The incidence of HPV was 53.2% for hrHPV and 22.32% for p16INK4a. hrHPV was not related to systemic or lymph node metastasis and locoregional recurrence, nor influenced the survival rate. P16INK4a seems to be a protective factor for death, which does not affect metastasis or tumor recurrence. Lymph node and systemic metastases and locoregional recurrence increase the risk of death. An increased 5mC mark was observed in penile SCC regardless of HPV infection. However, there is a reduction of the 5hmC mark for p16INK4a + (P = 0.024). Increased 5mC/5hmC ratio (> 1) was observed in 94.2% of penile SCC, irrespective of HPV infection. Despite the increase in 5mC, it seems not to affect the survival rate (HR = 1.06; 95% CI 0.33-3.38). P16INK4a seems to be a good prognosis marker for penile SCC and the increase in 5mC, an epigenetic mark of genomic stability, may support tumor progression leading to poor prognosis.

SUBMITTER: Santos RDS

PROVIDER: S-EPMC9597985 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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HPV infection and 5mC/5hmC epigenetic markers in penile squamous cell carcinoma: new insights into prognostics.

Santos Renan da Silva RDS Hirth Carlos Gustavo CG Pinheiro Daniel Pascoalino DP Bezerra Maria Júlia Barbosa MJB Silva-Fernandes Isabelle Joyce de Lima IJL Paula Dayrine Silveira de DS Alves Ana Paula Negreiros Nunes APNN Moraes Filho Manoel Odorico de MO Moura Arlindo de Alencar Araripe AAA Lima Marcos Venício Alves MVA Pessoa Claudia do Ó CDÓ Furtado Cristiana Libardi Miranda CLM

Clinical epigenetics 20221025 1

<h4>Background</h4>Penile cancer is one of the most aggressive male tumors. Although it is preventable, the main etiologic causes are lifestyle behaviors and viral infection, such as human papillomavirus (HPV). Long-term epigenetic changes due to environmental factors change cell fate and promote carcinogenesis, being an important marker of prognosis. We evaluated epidemiological aspects of penile squamous cell carcinoma (SCC) and the prevalence of HPV infection using high-risk HPV (hrHPV) and p ...[more]

PMID: 36284309

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Project description:Squamous cell carcinomas of the lower female genital tract may be human papillomavirus-associated or independent. We studied the HPV status, mutational repertoire, histology, and clinical data of 28 samples from 26 patients, 65% with a vulvar primary and 35% with a vaginal primary. These represented invasive vulvovaginal squamous cell carcinomas that underwent clinical tumor-normal targeted massively parallel sequencing analysis. HPV status was determined using the HPV high-risk RNA ISH assay and/or by MSK-IMPACT. Eleven patients had HPV-associated squamous cell carcinoma (four vulvar and seven vaginal) and 15 patients had HPV-independent SqCC (13 vulvar and 2 vaginal). Well-differentiated squamous cell carcinomas were always HPV-independent. HPV-independent moderately and poorly differentiated carcinomas frequently had alterations in the NOTCH signaling pathway (6/7), which were also associated with increased tumor budding (P: 0.002). HPV-associated vulvovaginal squamous cell carcinoma had PIK3CA activating mutations (7/11, 64%) as the most common genomic event, while TERT gene alterations, mainly TERT promoter mutations (14/15 cases, 93%) featured significantly in HPV-independent carcinomas. Other common abnormalities in HPV-independent tumors were TP53 mutations (13/15, 87%), CDKN2A alterations (10/15, 67%), and NOTCH1 and FAT1 mutations (7/15, 47% each). A subset of both HPV-associated and -independent tumors had NOTCH pathway alterations (6/11, 55% and 10/15, 67% respectively), but different genes in this pathway were altered in these tumors. In summary, TERT, TP53, CDKN2A, and NOTCH1 gene alterations strongly point away from an HPV-driven process (odds ratios: 0.01, 0.07, 0, and 0, respectively with p values < 0.02 for all four genes), while PIK3CA activating mutations without the other mutations strongly favors an HPV-driven tumor (odds ratio: 10.12, p value: 0.016). HPV-independent carcinomas are more likely to be moderately-poorly differentiated with intermediate to high tumor cell budding. Cancer cell fraction analysis of HPV-independent squamous carcinomas suggests that TERT and/or NOTCH1 alterations along with TP53 alterations can be the initiating event in these tumors.

Dataset Information

HPV infection and 5mC/5hmC epigenetic markers in penile squamous cell carcinoma: new insights into prognostics.

Publications

HPV infection and 5mC/5hmC epigenetic markers in penile squamous cell carcinoma: new insights into prognostics.

Similar Datasets

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