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
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Digital do Instituto Evandro Chagas (Patuá) |
Texto Completo: | https://patua.iec.gov.br/handle/iec/4080 |
Resumo: | 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 transcriptase‐quantitative 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 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. |
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Macedo, JulianaSilva, ElisNogueira, LeudivanCoelho, RonaldSilva, Jenilson daSantos, Alcione dosTeixeira Júnior, Antônio AugustoBelfort, MartaSilva, GylKhayat, AndréOliveira, Edivaldo Herculano Corrêa deSantos, Ana Paula dosCavalli, Luciane RPereira, Silma Regina2020-04-07T13:54:12Z2020-04-07T13:54:12Z2020MACEDO, Juliana et al. 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. Molecular Carcinogenesis, v. xx, n. xx, p. xx, 2020.0899-1987https://patua.iec.gov.br/handle/iec/408010.1002/mc.23185The 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 transcriptase‐quantitative 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 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.Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão. Grant Numbers: 00971/17, 01352/16.Federal University of Maranhão. Postgraduate Program in Health Science. São Luís, MA, Brazil.Federal University of Maranhão. Department of Biology. Laboratory of Genetics and Molecular Biology. São Luís, MA, Brazil.Aldenora Bello Cancer Hospital. São Luís, MA, Brazil.Aldenora Bello Cancer Hospital. São Luís, MA, Brazil.Federal University of Maranhão. Postgraduate Program in Health Science. São Luís, MA, Brazil / Federal University of Maranhão. Department of Biology. Laboratory of Genetics and Molecular Biology. São Luís, MA, Brazil.Federal University of Maranhão. Public Health Department. São Luís, MA, Brazil.Federal University of Maranhão. Department of Pathology. Biology Undergraduate Course. São Luís, MA, Brazil.Federal University of Maranhão. Postgraduate Program in Health Science. São Luís, MA, Brazil.Federal University of Maranhão. Department of Pathology. Biology Undergraduate Course. São Luís, MA, Brazil.Federal University of Pará. Oncology Research Center. Belém, PA, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Laboratório de Cultura de Tecido e citogenética. Ananindeua, PA, Brasil.Federal University of Maranhão. Department of Physiological Sciences. São Luís, MA, Brazil.Faculdades Pequeno Príncipe. Instituto de Pesquisa Pelé Pequeno Príncipe. Curitiba, PR, Brazil / Georgetown Lombardi Comprehensive Cancer Center. Department of Oncology. Washington, District of Columbia, United States.Federal University of Maranhão. Department of Biology. Laboratory of Genetics and Molecular Biology. São Luís, MA, Brazil.engWileyGenomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancerinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleNeoplasias Penianas / patologiaCarcinomaPênis / anatomia & histologiaDoenças do PênisInfecções por Papillomavirus / genéticaTécnicas de Genotipagem / MétodosBiomarcadores Tumoraisinfo:eu-repo/semantics/embargoedAccessreponame:Repositório Digital do Instituto Evandro Chagas (Patuá)instname:Instituto Evandro Chagas (IEC)instacron:IECORIGINALGenomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer.pdfGenomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer.pdfapplication/pdf551083https://patua.iec.gov.br/bitstreams/cf34599d-9465-4528-a925-5f4bb6efc9c7/downloadc9a9c128e29cac82a5d7fdf3f4e6da73MD51LICENSElicense.txtlicense.txttext/plain; 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dc.title.pt_BR.fl_str_mv |
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 |
title |
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 |
spellingShingle |
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, Juliana Neoplasias Penianas / patologia Carcinoma Pênis / anatomia & histologia Doenças do Pênis Infecções por Papillomavirus / genética Técnicas de Genotipagem / Métodos Biomarcadores Tumorais |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
author |
Macedo, Juliana |
author_facet |
Macedo, Juliana Silva, Elis Nogueira, Leudivan Coelho, Ronald Silva, Jenilson da Santos, Alcione dos Teixeira Júnior, Antônio Augusto Belfort, Marta Silva, Gyl Khayat, André Oliveira, Edivaldo Herculano Corrêa de Santos, Ana Paula dos Cavalli, Luciane R Pereira, Silma Regina |
author_role |
author |
author2 |
Silva, Elis Nogueira, Leudivan Coelho, Ronald Silva, Jenilson da Santos, Alcione dos Teixeira Júnior, Antônio Augusto Belfort, Marta Silva, Gyl Khayat, André Oliveira, Edivaldo Herculano Corrêa de Santos, Ana Paula dos Cavalli, Luciane R Pereira, Silma Regina |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Macedo, Juliana Silva, Elis Nogueira, Leudivan Coelho, Ronald Silva, Jenilson da Santos, Alcione dos Teixeira Júnior, Antônio Augusto Belfort, Marta Silva, Gyl Khayat, André Oliveira, Edivaldo Herculano Corrêa de Santos, Ana Paula dos Cavalli, Luciane R Pereira, Silma Regina |
dc.subject.decsPrimary.pt_BR.fl_str_mv |
Neoplasias Penianas / patologia Carcinoma Pênis / anatomia & histologia Doenças do Pênis Infecções por Papillomavirus / genética Técnicas de Genotipagem / Métodos Biomarcadores Tumorais |
topic |
Neoplasias Penianas / patologia Carcinoma Pênis / anatomia & histologia Doenças do Pênis Infecções por Papillomavirus / genética Técnicas de Genotipagem / Métodos Biomarcadores Tumorais |
description |
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 transcriptase‐quantitative 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 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. |
publishDate |
2020 |
dc.date.accessioned.fl_str_mv |
2020-04-07T13:54:12Z |
dc.date.available.fl_str_mv |
2020-04-07T13:54:12Z |
dc.date.issued.fl_str_mv |
2020 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
MACEDO, Juliana et al. 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. Molecular Carcinogenesis, v. xx, n. xx, p. xx, 2020. |
dc.identifier.uri.fl_str_mv |
https://patua.iec.gov.br/handle/iec/4080 |
dc.identifier.issn.-.fl_str_mv |
0899-1987 |
dc.identifier.doi.-.fl_str_mv |
10.1002/mc.23185 |
identifier_str_mv |
MACEDO, Juliana et al. 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. Molecular Carcinogenesis, v. xx, n. xx, p. xx, 2020. 0899-1987 10.1002/mc.23185 |
url |
https://patua.iec.gov.br/handle/iec/4080 |
dc.language.iso.fl_str_mv |
eng |
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eng |
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info:eu-repo/semantics/embargoedAccess |
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dc.publisher.none.fl_str_mv |
Wiley |
publisher.none.fl_str_mv |
Wiley |
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