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The molecular mechanisms that underly the onset and progression of these tumors are still unclear. Therefore, our goal was to determine the genome\u2010wide copy number alterations and the involvement of human papiloma virus (HPV) (<jats:italic>TP53<\/jats:italic> and <jats:italic>RB1)<\/jats:italic>, inflammatory (<jats:italic>COX2<\/jats:italic> and <jats:italic>EGFR<\/jats:italic>), and PI3K\/AKT pathway (<jats:italic>AKT1<\/jats:italic>, <jats:italic>AKT2<\/jats:italic>, <jats:italic>EGFR<\/jats:italic>, <jats:italic>ERBB3<\/jats:italic>, <jats:italic>ERBB4<\/jats:italic>, <jats:italic>PIK3CA<\/jats:italic>, and <jats:italic>PTEN<\/jats:italic>) associated genes in patients with PeCa from a high incidence region in Brazil (Maranh\u00e3o). HPV genotyping was performed by nest\u2010PCR and genome sequencing, copy number alterations (CNAs) by array comparative genomic hybridization and gene copy number <jats:italic>status<\/jats:italic>, gene, and protein expression by quantitative polymerase chain reaction, reverse transcriptase\u2010quantitative 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\u2010p11.2 and 14q32.33, where ADAM 6, KIAA0125, LINC00226, LINC00221, and miR7641\u20102, are mapped. Increased copy number of <jats:italic>ERBB3<\/jats:italic> and <jats:italic>EGFR<\/jats:italic> genes were observed in association with COX2 and EGFR overexpression, reinforcing the role of the inflammatory pathway in PeCa, and suggesting anti\u2010EGFR and anti\u2010COX2 inhibitors as promising therapies for PeCa. Additionally, <jats:italic>TP53<\/jats:italic> and <jats:italic>RB1<\/jats:italic> 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\u2010associated carcinomas and suggest the pivotal role of HPV driving CNAs and controlling gene expression in PeCa.<\/jats:p>","DOI":"10.1002\/mc.23185","type":"journal-article","created":{"date-parts":[[2020,3,25]],"date-time":"2020-03-25T06:25:16Z","timestamp":1585117516000},"page":"604-617","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of <i>TP53<\/i> and <i>RB1<\/i> in penile cancer"],"prefix":"10.1002","volume":"59","author":[{"given":"Juliana","family":"Macedo","sequence":"first","affiliation":[{"name":"Postgraduate Program in Health Science, Federal University of Maranh\u00e3o  S\u00e3o Lu\u00eds Maranh\u00e3o 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