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In PSCC, for which the incidence has progressively increased worldwide, there are still limited data on the molecular mechanisms involved in the disease pathogenesis. In this study, we characterized the mutational signature of 30 human papillomavirus (HPV)-associated PSCC cases from Latin Americans, using whole-exome sequencing. Copy number variations (CNVs) were also identified and compared to previous array-generated data. Enrichment analyses were performed to reveal disrupted pathways and to identify alterations mapped to HPV integration sites (HPVis) and miRNA\u2013mRNA hybridization regions. Among the most frequently mutated genes were NOTCH1, TERT, TTN, FAT1, TP53, CDKN2A, RYR2, CASP8, FBXW7, HMCN2, and ITGA8. Of note, 92% of these altered genes were localized at HPVis. We also found mutations in ten novel genes (KMT2C, SMARCA4, PTPRB, AJUBA, CR1, KMT2D, NBEA, FAM135B, GTF2I, and CIC), thus increasing our understanding of the potential HPV-disrupted pathways. Therefore, our study reveals innovative targets with potential therapeutic benefits for HPV-associated PSCCs. The CNV analysis by sequencing (CNV-seq) revealed five cancer-associated genes as the most frequent with gains (NOTCH1, MYC, NUMA1, PLAG1, and RAD21), while 30% of the tumors showed SMARCA4 with loss. Additionally, four cancer-associated genes (CARD11, CSMD3, KDR, and TLX3) carried untranslated regions (UTRs) variants, which may impact gene regulation by affecting the miRNAs hybridization regions. Altogether, these data contribute to the characterization of the mutational spectrum and its impact on cellular signaling pathways in PSCC, thus reinforcing the pivotal role of HPV infection in the molecular pathogenesis of these tumors.<\/jats:p>","DOI":"10.3390\/cancers14143514","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T23:10:22Z","timestamp":1658272222000},"page":"3514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-9431","authenticated-orcid":false,"given":"Luisa Matos","family":"Canto","sequence":"first","affiliation":[{"name":"Clinical Genetics Department, University Hospital of Southern Denmark, 7100 Vejle, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenilson Mota","family":"da Silva","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Health Science, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"},{"name":"Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patr\u00edcia Val\u00e8ria","family":"Castelo-Branco","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid Monteiro","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leudivan","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Aldenora Bello Cancer Hospital, S\u00e3o Lu\u00eds 65031-630, MA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6702-6139","authenticated-orcid":false,"given":"Carlos Eduardo","family":"Fonseca-Alves","sequence":"additional","affiliation":[{"name":"Health Science Institute, Paulista University, Bauru 186085-500, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9","family":"Khayat","sequence":"additional","affiliation":[{"name":"Oncology Research Center, Federal University of Par\u00e1, Bel\u00e9m 66073-005, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1015-2561","authenticated-orcid":false,"given":"Alexander","family":"Birbrair","sequence":"additional","affiliation":[{"name":"Department of Dermatology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA"},{"name":"Department of Pathology, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, Brazil"},{"name":"Department of Radiology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silma Regina","family":"Pereira","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, MA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.cell.2018.03.035","article-title":"Oncogenic Signaling Pathways in The Cancer Genome Atlas","volume":"173","author":"Mina","year":"2018","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41586-020-1943-3","article-title":"The Repertoire of Mutational Signatures in Human Cancer","volume":"578","author":"Alexandrov","year":"2020","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41572-021-00246-5","article-title":"Penile Cancer","volume":"7","author":"Thomas","year":"2021","journal-title":"Nat. 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