Genome-wide methylation and transcriptome analysis in penile carcinoma: uncovering new molecular markers

Kuasne, Hellen; Cólus, Ilce Mara de Syllos; Busso, Ariane Fidelis; Hernandez-Vargas, Héctor; Barros-Filho, Mateus Camargo; Marchi, Fábio Albuquerque; Scapulatempo‐Neto, Cristovam; Faria, Eliney Ferreira; Lopes, Ademar; Guimarães, Gustavo Cardoso; Herceg, Zdenko; Rogatto, Sílvia Regina

doi:10.1186/s13148-015-0082-4

Cited by 47 publications

(55 citation statements)

References 33 publications

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“…Functional loss of the AR gene by promoter hypermethylation has been described as involved in PeCa development [31]. A previous study by our group on penile tumors did not reveal AR hypermethylation [18]. In addition to hypermethylation, dysregulation of the miRNAs that target AR may also contribute to PeCa development and progression.…”

Section: Discussionmentioning

confidence: 99%

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Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

et al. 2017

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Penile carcinoma (PeCa) is an important public health issue in poor and developing countries, and has only recently been explored in terms of genetic and epigenetic studies. Integrative data analysis is a powerful method for the identification of molecular drivers involved in cancer development and progression. miRNA and mRNA expression profiles followed by integrative analysis were investigated in 23 PeCa and 12 non-neoplastic penile tissues (NPT). Expression levels of eight miRNAs and 10 mRNAs were evaluated in the same set of samples used for microarray and in a validation set of cases (PeCa = 36; NPT = 27). Eighty-one miRNAs and 2,697 mRNAs were identified as differentially expressed in PeCa. Integrative data analysis revealed 255 mRNAs potentially regulated by 68 miRNAs. Using RT-qPCR, eight miRNAs and nine transcripts were confirmed as altered in PeCa. We identified that MMP1, MMP12 and PPARG and hsa-miR-31-5p, hsa-miR-224-5p, and hsa-miR-223-3p were able to distinguish tumors from NPT with high sensitivity and specificity. Higher MMP1 expression was detected as a better predictor of lymph node metastasis than the clinical-pathological data. In addition, PPARG and EGFR were highlighted as potential pathways for targeted therapy in PeCa. The analysis based on HPV positivity (7 of 23 cases) revealed five miRNA and 13 mRNA differentially expressed. Although in a limited number of cases, HPV positive PeCa presented less aggressive phenotype in comparison with negative cases. Overall, an integrative analysis using mRNA and miRNA profiles revealed markers related with tumor development and progression. Furthermore, MMP1 expression level was a predictive marker for lymph node metastasis in patients with PeCa.

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Section: Discussionmentioning

confidence: 99%

“…[18] Transcriptomic data are available on the Gene Expression Omnibus (GEO) database (GSE57955). Unsupervised hierarchical clustering analysis of miRNA and mRNA expression was accomplished using one minus correlation metric and complete linkage.…”

Section: Methodsmentioning

confidence: 99%

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

et al. 2017

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“…1,11,12 Other molecular mechanisms have been described, including new targets of E6 and E7 oncoproteins, which might interact or modulate the activity of proteins involved in the epigenetic regulation or in the differential expression of host cell miRNAs. [13][14][15][16][17] In parallel, the chronic inflammatory process has been investigated as a risk factor to PeCa, which can be triggered by phimosis, lichen sclerosus, and balanitis. [18][19][20][21] This process can provide a favorable microenvironment for malignant cell transformation and progression due to the release of reactive oxygen or nitrogen species, as well due to the extensive tissue damage and remodeling that is mediated by the immune system cells.…”

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confidence: 99%

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

Macedo

Silva

Nogueira³

et al. 2020

Molecular Carcinogenesis

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The incidence of penile cancer (PeCa) is increasing worldwide, however, the highest rates are reported in underdeveloped countries. The molecular mechanisms that underly the onset and progression of these tumors are still unclear. Therefore, our goal was to determine the genome-wide copy number alterations and the involvement of human papiloma virus (HPV) (TP53 and RB1), inflammatory (COX2 and EGFR), and PI3K/AKT pathway (AKT1, AKT2, EGFR, ERBB3, ERBB4, PIK3CA, and PTEN) associated genes in patients with PeCa from a high incidence region in Brazil (Maranhão). HPV genotyping was performed by nest-PCR and genome sequencing, copy number alterations (CNAs) by array comparative genomic hybridization and gene copy number status, gene, and protein expression by quantitative polymerase chain reaction, reverse transcriptasequantitative polymerase chain reaction, and immunohistochemistry, respectively.HPV genotyping revealed one of the highest frequencies of HPV reported in PeCa, affecting 96.4% of the cases. The most common CNAs observed were located at the HPV integration sites, such as 2p12-p11.2 and 14q32.33, where Abbreviations: aCGH, array comparative genomic hybridization; CNA, copy number alteration; Cq, quantification cycle; FFPE, formalin-fixed paraffin-embedded; HPV, human papiloma virus;HrHPV, High risk HPV; IHCi, mmunohistochemistry; PCR, polymerase chain reaction; PeCa, penile cancer; qPCR, quantitative polymerase chain reaction; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction; TMA, tissue microarray. ADAM 6, KIAA0125, LINC00226, LINC00221, and miR7641-2, are mapped. Increased copy number of ERBB3 and EGFR genes were observed in association with COX2 and EGFR overexpression, reinforcing the role of the inflammatory pathway in PeCa, and suggesting anti-EGFR and anti-COX2 inhibitors as promising therapies for PeCa. Additionally, TP53 and RB1 messenger RNA downregulation was observed, suggesting the occurrence of other mechanisms for repression of these oncoproteins, in addition to the canonical HPV/TP53/RB1 signaling pathway. Our data reinforce the role of epigenetic events in abnormal gene expression in HPV-associated carcinomas and suggest the pivotal role of HPV driving CNAs and controlling gene expression in PeCa. K E Y W O R D Scarcinoma of the penis, genomic alterations, human papillomavirus, molecular markers

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“…CpG hypermethylation of SOX3 and its underexpression in penile carcinoma tissue were reported by Kuasne et al [2015]. Methylation of CpGI in the 5 ′ UTR of murine Sox9 showed different profiles in testis and ovaries [Pamnani et al, 2016].…”

Section: Discussionmentioning

confidence: 99%

Methylation Patterns of SOX3, SOX9, and WNT4 Genes in Gonads of Dogs with XX (SRY-Negative) Disorder of Sexual Development

Salamon

Flisikowski²,

Świtoński³

2017

Sex Dev

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Ovotesticular or testicular disorder of sexual development in dogs with female karyotype and lack of SRY (XX DSD) is a common sexual anomaly diagnosed in numerous breeds. The molecular background, however, remains unclear, and epigenetic mechanisms, including DNA methylation, have not been studied. The aim of our study was comparative methylation analysis of CpG islands in promoters of candidate genes for XX DSD: SOX9, SOX3, and WNT4. Methylation studies were performed on DNA extracted from formalin-fixed/paraffin-embedded or frozen gonads from 2 dogs with ovotesticular and 2 dogs with testicular XX DSD as well as control females (n = 4) and males (n = 2). Bisulfite-converted DNA was used for CpG methylation analysis using quantitative pyrosequencing. Promoter regions of SOX9 and WNT4 showed similar CpG methylation in each group, ranging from 0 to 5.5% and from 39 to 74%, respectively. The SOX3 promoter showed significantly higher methylation in the ovotesticular XX DSD cases and the testicular XX DSD and control males, suggesting that SOX3 methylation may play a role in canine XX DSD pathogenesis.

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Genome-wide methylation and transcriptome analysis in penile carcinoma: uncovering new molecular markers

Cited by 47 publications

References 33 publications

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

Methylation Patterns of <b><i>SOX3, SOX9</i></b>, and <b><i>WNT4</i></b> Genes in Gonads of Dogs with XX (<b><i>SRY</i></b>-Negative) Disorder of Sexual Development

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