Epigenetic Mechanisms in Penile Carcinoma

Kuasne, Hellen; Marchi, Fábio Albuquerque; Rogatto, Sílvia Regina; Cólus, Ilce Mara de Syllos

doi:10.3390/ijms140610791

Cited by 17 publications

(11 citation statements)

References 110 publications

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“…The distinct genomic profile between HPV-positive and -negative samples gives additional support for the hypothesis that these tumors have two distinct etiologies: one dependent and the other independent of HPV infection (11,32,33). The regions frequently detected as altered in HPV-positive cases must be further explored, aiming to better understand the involvement of HPV in penile carcinoma and its potential application in clinical practice.…”

Section: Discussionmentioning

confidence: 94%

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Genomic Profiling of Human Penile Carcinoma Predicts Worse Prognosis and Survival

Busso-Lopes

Marchi

Kuasne

et al. 2015

Cancer Prevention Research

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The molecular mechanisms underlying penile carcinoma are still poorly understood, and the detection of genetic markers would be of great benefit for these patients. In this study, we assessed the genomic profile aiming at identifying potential prognostic biomarkers in penile carcinoma. Globally, 46 penile carcinoma samples were considered to evaluate DNA copynumber alterations via array comparative genomic hybridization (aCGH) combined with human papillomavirus (HPV) genotyping. Specific genes were investigated by using qPCR, FISH, and RT-qPCR. Genomic alterations mapped at 3p and 8p were related to worse prognostic features, including advanced T and clinical stage, recurrence and death from the disease. Losses of 3p21.1-p14.3 and gains of 3q25.31-q29 were associated with reduced cancer-specific and disease-free survival. Genomic alterations detected for chromosome 3 (LAMP3, PPARG, TNFSF10 genes) and 8 (DLC1) were evaluated by qPCR. DLC1 and PPARG losses were associated with poor prognosis characteristics. Losses of DLC1 were an independent risk factor for recurrence on multivariate analysis. The gene-expression analysis showed downexpression of DLC1 and PPARG and overexpression of LAMP3 and TNFSF10 genes. Chromosome Y losses and MYC gene (8q24) gains were confirmed by FISH. HPV infection was detected in 34.8% of the samples, and 19 differential genomic regions were obtained related to viral status. At first time, we described recurrent copy-number alterations and its potential prognostic value in penile carcinomas. We also showed a specific genomic profile according to HPV infection, supporting the hypothesis that penile tumors present distinct etiologies according to virus status.

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Section: Discussionmentioning

confidence: 94%

“…Mutations for PIK3CA, HRAS, KRAS, TP53, and CDKN2A, as well as methylation of CpG islands in particular genes, including FHIT, RUNX3, CDKN2A, and THBS-1, have been reported (10,11). Even fewer studies have described an association between genetic alterations and clinical findings.…”

Section: Introductionmentioning

confidence: 99%

Genomic Profiling of Human Penile Carcinoma Predicts Worse Prognosis and Survival

Busso-Lopes

Marchi

Kuasne

et al. 2015

Cancer Prevention Research

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“…The data used for integrative analysis were obtained from previous studies of our group 14 , 22 , 42 . Genome-wide copy number alteration analysis was performed using Agilent Human 4 × 44 K CGH Microarrays (Agilent Technologies) 42 .…”

Section: Methodsmentioning

confidence: 99%

“…Penile carcinoma (PeCa) is a rare genitourinary malignancy in developed countries, with an incidence of 0.2 per 100,000 men in the United States and Europe 11 , 12 and 2.9 to 6.8 cases per 100,000 in the Brazilian population 13 . The risk factors described in PeCa include phimosis with chronic inflammation, poor hygiene, smoking, low socioeconomic status, number of sexual partners, a history of genital warts and/or other sexually transmitted diseases 14 . Approximately 40% of PeCa are HPV positive, however, the impact of high-risk HPV in the prognosis has not been clarified 15 .…”

Section: Introductionmentioning

confidence: 99%

Multidimensional integrative analysis uncovers driver candidates and biomarkers in penile carcinoma

Marchi

Martins

Barros-Filho

et al. 2017

Sci Rep

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Molecular data generation and their combination in penile carcinomas (PeCa), a significant public health problem in poor and underdeveloped countries, remain virtually unexplored. An integrativemethodology combin ing genome-wide copy number alteration, DNA methylation, miRNA and mRNA expression analysis was performed in a set of 20 usual PeCa. The well-ranked 16 driver candidates harboring genomic alterations and regulated by a set of miRNAs, including hsa-miR-31, hsa-miR-34a and hsa-miR-130b, were significantly associated with over-represented pathways in cancer, such as immune-inflammatory system, apoptosis and cell cycle. Modules of co-expressed genes generated from expression matrix were associated with driver candidates and classified according to the over-representation of passengers, thus suggesting an alteration of the pathway dynamics during the carcinogenesis. This association resulted in 10 top driver candidates (AR, BIRC5, DNMT3B, ERBB4, FGFR1, PML, PPARG, RB1, TNFSF10 and STAT1) selected and confirmed as altered in an independent set of 33 PeCa samples. In addition to the potential driver genes herein described, shorter overall survival was associated with BIRC5 and DNMT3B overexpression (log-rank test, P = 0.026 and P = 0.002, respectively) highlighting its potential as novel prognostic marker for penile cancer.

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“…Hypermethylation of the CDK2A gene promoter was found to be present in 15–42% of PeCa samples [109]. Feber et al [110] evaluated the methylation profile of 38 PeCa samples using high-density genome-wide methylation arrays.…”

Section: Targeting Dnmts In Genitourinary Cancermentioning

confidence: 99%

Incorporating DNA Methyltransferase Inhibitors (DNMTis) in the Treatment of Genitourinary Malignancies: A Systematic Review

et al. 2017

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Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hypermethylation in promoters of critical tumor suppressor genes is the basis for the idea that treatment with hypomethylating agents may lead to the restoration of a "normal" epigenome and produce clinically meaningful therapeutic outcomes. The aim of this review article is to summarize the current state of knowledge of DNMT inhibitors in the treatment of genitourinary malignancies. The efficacy of these agents in genitourinary malignancies was reported in a number of studies and suggests a role of induced DNA hypomethylation in overcoming resistance to conventional cytotoxic treatments. The clinical significance of these findings should be further investigated.

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Epigenetic Mechanisms in Penile Carcinoma

Cited by 17 publications

References 110 publications

Genomic Profiling of Human Penile Carcinoma Predicts Worse Prognosis and Survival

Genomic Profiling of Human Penile Carcinoma Predicts Worse Prognosis and Survival

Multidimensional integrative analysis uncovers driver candidates and biomarkers in penile carcinoma

Incorporating DNA Methyltransferase Inhibitors (DNMTis) in the Treatment of Genitourinary Malignancies: A Systematic Review

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