Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients

Luisa Matos do Canto, Jenilson Mota da Silva, Patrícia Valèria Castelo-Branco, Ingrid Monteiro da Silva, Leudivan Nogueira, Carlos Eduardo Fonseca-Alves, André Khayat, Alexander Birbrair, Silma Regina Pereira*

*Kontaktforfatter

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Abstract

High-throughput DNA sequencing has allowed for the identification of genomic alterations and their impact on tumor development, progression, and therapeutic responses. 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–mRNA 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.

OriginalsprogEngelsk
Artikelnummer3514
TidsskriftCancers
Vol/bind14
Udgave nummer14
Antal sider20
ISSN2072-6694
DOI
StatusUdgivet - jul. 2022

Bibliografisk note

Funding Information:
We are grateful to the Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, for the technical assistance with Whole-exome sequencing. The authors are also thankful to the Hospital Albert Einstein/VarStation for the Bioinformatics service. We are grateful to Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA) for funding this research and to Coordenação de Aperfeiçoamento Pessoal de Nível Superior (CAPES-code 001) for providing scholarship to J.M.S. (Master Postgraduate Program in Health Science, Federal University of Maranhão, Brazil).

Funding Information:
This research was funded by Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA; Grant #COOPI-07895/17 and IECT-05551/18) and by Coordenação de Aperfeiçoamento Pessoal de Nível Superior (CAPES- code 001). “The APC was partially funded by Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA) POSGRAD 02598/21”.

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