Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients
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 inv...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/14/3514 |
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| author | Luisa Matos 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 |
| author_facet | Luisa Matos 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 |
| author_sort | Luisa Matos Canto |
| collection | DOAJ |
| description | 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 <i>NOTCH1</i>, <i>TERT</i>, <i>TTN</i>, <i>FAT1</i>, <i>TP53</i>, <i>CDKN2A</i>, <i>RYR2</i>, <i>CASP8</i>, <i>FBXW7</i>, <i>HMCN2</i>, and <i>ITGA8</i>. Of note, 92% of these altered genes were localized at HPVis. We also found mutations in ten novel genes (<i>KMT2C</i>, <i>SMARCA4</i>, <i>PTPRB</i>, <i>AJUBA</i>, <i>CR1</i>, <i>KMT2D</i>, <i>NBEA</i>, <i>FAM135B</i>, <i>GTF2I</i>, and <i>CIC</i>), 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 (<i>NOTCH1</i>, <i>MYC</i>, <i>NUMA1</i>, <i>PLAG1</i>, and <i>RAD21</i>), while 30% of the tumors showed <i>SMARCA4</i> with loss. Additionally, four cancer-associated genes (<i>CARD11</i>, <i>CSMD3</i>, <i>KDR</i>, and <i>TLX3</i>) 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. |
| first_indexed | 2024-03-09T03:37:00Z |
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| id | doaj.art-f56d15a9da36433ba65d3c1f0d47aab6 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T03:37:00Z |
| publishDate | 2022-07-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-f56d15a9da36433ba65d3c1f0d47aab62023-12-03T14:48:09ZengMDPI AGCancers2072-66942022-07-011414351410.3390/cancers14143514Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American PatientsLuisa Matos Canto0Jenilson Mota da Silva1Patrícia Valèria Castelo-Branco2Ingrid Monteiro da Silva3Leudivan Nogueira4Carlos Eduardo Fonseca-Alves5André Khayat6Alexander Birbrair7Silma Regina Pereira8Clinical Genetics Department, University Hospital of Southern Denmark, 7100 Vejle, DenmarkPostgraduate Program in Health Science, Federal University of Maranhão, São Luís 65080-805, MA, BrazilLaboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, São Luís 65080-805, MA, BrazilLaboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, São Luís 65080-805, MA, BrazilAldenora Bello Cancer Hospital, São Luís 65031-630, MA, BrazilHealth Science Institute, Paulista University, Bauru 186085-500, SP, BrazilOncology Research Center, Federal University of Pará, Belém 66073-005, PA, BrazilDepartment of Dermatology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USALaboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, São Luís 65080-805, MA, BrazilHigh-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 <i>NOTCH1</i>, <i>TERT</i>, <i>TTN</i>, <i>FAT1</i>, <i>TP53</i>, <i>CDKN2A</i>, <i>RYR2</i>, <i>CASP8</i>, <i>FBXW7</i>, <i>HMCN2</i>, and <i>ITGA8</i>. Of note, 92% of these altered genes were localized at HPVis. We also found mutations in ten novel genes (<i>KMT2C</i>, <i>SMARCA4</i>, <i>PTPRB</i>, <i>AJUBA</i>, <i>CR1</i>, <i>KMT2D</i>, <i>NBEA</i>, <i>FAM135B</i>, <i>GTF2I</i>, and <i>CIC</i>), 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 (<i>NOTCH1</i>, <i>MYC</i>, <i>NUMA1</i>, <i>PLAG1</i>, and <i>RAD21</i>), while 30% of the tumors showed <i>SMARCA4</i> with loss. Additionally, four cancer-associated genes (<i>CARD11</i>, <i>CSMD3</i>, <i>KDR</i>, and <i>TLX3</i>) 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.https://www.mdpi.com/2072-6694/14/14/3514whole-exome sequencingHPVpeniscarcinomabiomarkers |
| spellingShingle | Luisa Matos 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 Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients Cancers whole-exome sequencing HPV penis carcinoma biomarkers |
| title | Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients |
| title_full | Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients |
| title_fullStr | Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients |
| title_full_unstemmed | Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients |
| title_short | Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients |
| title_sort | mutational signature and integrative genomic analysis of human papillomavirus associated penile squamous cell carcinomas from latin american patients |
| topic | whole-exome sequencing HPV penis carcinoma biomarkers |
| url | https://www.mdpi.com/2072-6694/14/14/3514 |
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