Análise integrativa do perfil multi omico dos canceres de mama e prostata
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Data
2022-12-02
Autores
Campolino, Luana Moura
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Nas últimas décadas vem sendo observado um acréscimo significativo na incidência de canceres na população mundial, este fato está diretamente relacionado com dieta, sedentarismo, tabagismo, senilidade, poluição e adversidades no desenvolvimento embrionário. Os mais recorrentes são os canceres de próstata (CaP) e mama (CaM) em homens e mulheres, respectivamente, excluindo-se câncer de pele não-melanoma. A próstata e a mama são glândulas acessórias do sistema genital, com homeostasia e processos patológicos regulados sob controle hormonal. Considera-se que CaP e CaM, apresentam certa similaridade em mecanismos epigenéticos e genéticos que vão desde a morfogênese, até a progressão tumoral. Todavia, mesmo com o advento das multiômicas, não há trabalhos integrando perfis globais de eventos genéticos e epigenéticos que contribuem para a carcinogênese dos tecidos reprodutivos, sendo assim o objetivo desse trabalho foi identificar os mecanismos genéticos e epigenéticos, comumente desregulados nos CaP e CaM, buscando identificar assinaturas epigenéticas, vias moleculares e potenciais alvos terapêuticos. Para isso, foram utilizados dados de sequenciamento de última geração de mRNA, miRNA e metilação de DNA, advindos do The Cancer Genome Atlas (TCGA), dos estudos de CaP (PRAD-TCGA, 498 amostras tumorais e 52 controles) e CaM (BRCA-TCGA, 1085 amostras tumorais e 112 controles). Foram considerados diferencialmente expressos (DE) mRNAs e miRNAs cujo log2 de fold change > |±1| e FDR > 0,01. Os dados globais de metilação foram considerados diferencialmente metilados com β-value > |±0,25| e FDR > 0,01. Foram integrados dados de miRNA-mRNA de CaP e CaM na plataforma miRWalk 3.0. As integrações metilação mRNA foram realizadas a partir da correlação entre Log2 de fold change e βvalue. A identificação das vias moleculares fora realizada através da ferramenta Kobas 3.0, a rede de interação entre os alvos foi realizada na plataforma String, e as curvas de sobrevida e análises genômicas no cBioportal e as validações in vivo foram realizadas no The Human Protein Atlas. CaP e CaM demonstraram 1.325 genes em comum (1.047 down e 278 up). 78 miRNAs foram comumente desregulados (7 down e 71 up), além de 2.887 regiões metiladas (556 hipo e 2.331 hiper). A integração entre miRNAs e mRNAs validados reportaram 8 miRNAs regulando 9 mRNAs; e a integração entre a metilação e os mRNAs mostraram 229 genes down regulados com hipermetilação no DNA e 7 genes up regulados com hipometilação. As vias moleculares foram agrupadas de acordo com funções. Dos genes regulados por metilação foram identificados 3 cluster de interação PPI, com 12 genes interagindo entre si. Em Oncoprint foi evidenciado alterações genômicas e vimos seus impactos na sobrevida dos pacientes, sendo a Angiopoietina- 1 (ANGPT1) mais alterado nesses pacientes. A validação in silico no HPA mostrou que a ANGPT1 desregulada nos tecidos tumorais de CaP e CaM. Nossos dados sugerem potenciais mecanismos genéticos e epigenéticos como assinaturas CaP e CaM, sendo a ANGPT1 um bom alvo para mais estudos, acreditamos que um maior entendimento acerca desse gene e sua relação com a evolução dos canceres de próstata e mama possa ser um importante passo para descobertas de alvos terapêuticos efetivos.
In recent decades, a significant increase in the incidence of cancers in the world population has been observed. This fact is directly related to diet, sedentary lifestyle, smoking, senility, pollution, and adversities in embryonic development. The most recurrent are prostate (PCa) and breast (BC) cancers in men and women, respectively, excluding non-melanoma skin cancer. The prostate and breast are accessory glands of the genital system, with homeostasis and pathological processes regulated under hormonal control. CaP and CaM are considered to have a certain similarity in epigenetic and genetic mechanisms that range from morphogenesis to tumor progression. However, even with the advent of multi-omics, there are no studies integrating global profiles of genetic and epigenetic events that contribute to carcinogenesis of reproductive tissues, thus the aim of this study was to identify genetic and epigenetic mechanisms, commonly deregulated in CaP and CaM, seeking to identify epigenetic signatures, molecular pathways and potential therapeutic targets. To this end, next-generation mRNA, miRNA and DNA methylation sequencing data from The Cancer Genome Atlas (TCGA) were used from studies of CaP (PRAD-TCGA, 498 tumor samples and 52 controls) and CaM (BRCA-TCGA, 1085 tumor samples and 112 controls). Differentially expressed (DE) mRNAs and miRNAs whose log2 of fold change > |±1| and FDR > 0.01 were considered. Global methylation data were considered differentially methylated with β-value > |±0.25| and FDR > 0.01. CaP and CaM miRNA-mRNA data were integrated into the miRWalk 3.0 platform. The mRNA methylation integrations were performed from the correlation between Log2 of fold change and βvalue. Molecular pathway identification had been performed using the Kobas 3.0 tool, target interaction networking was performed on the String platform, and survival curves and genomic analyses on cBioportal and in vivo validations were performed on The Human Protein Atlas. CaP and CaM demonstrated 1,325 genes in common (1,047 down and 278 up). 78 miRNAs were commonly downregulated (7 down and 71 up), in addition to 2,887 methylated regions (556 hypo and 2,331 hyper). Integration between miRNAs and validated mRNAs reported 8 miRNAs regulating 9 mRNAs; and integration between methylation and mRNAs showed 229 down regulated genes with hypermethylation in DNA and 7 up regulated genes with hypomethylation. The molecular pathways were grouped according to functions. Of the methylation regulated genes, 3 PPI interaction clusters were identified, with 12 genes interacting with each other. In Oncoprint genomic alterations were evidenced and we saw their impacts on patient survival, with Angiopoietin-1 (ANGPT1) being most altered in these patients. In silico validation in HPA showed that ANGPT1 downregulated in CaP and CaM tumor tissues. Our data suggest potential genetic and epigenetic mechanisms as CaP and CaM signatures, with ANGPT1 being a good target for further study, we believe that a greater understanding about this gene and its relationship with the evolution of prostate and breast cancers may be an important step towards discoveries of effective therapeutic targets.
In recent decades, a significant increase in the incidence of cancers in the world population has been observed. This fact is directly related to diet, sedentary lifestyle, smoking, senility, pollution, and adversities in embryonic development. The most recurrent are prostate (PCa) and breast (BC) cancers in men and women, respectively, excluding non-melanoma skin cancer. The prostate and breast are accessory glands of the genital system, with homeostasis and pathological processes regulated under hormonal control. CaP and CaM are considered to have a certain similarity in epigenetic and genetic mechanisms that range from morphogenesis to tumor progression. However, even with the advent of multi-omics, there are no studies integrating global profiles of genetic and epigenetic events that contribute to carcinogenesis of reproductive tissues, thus the aim of this study was to identify genetic and epigenetic mechanisms, commonly deregulated in CaP and CaM, seeking to identify epigenetic signatures, molecular pathways and potential therapeutic targets. To this end, next-generation mRNA, miRNA and DNA methylation sequencing data from The Cancer Genome Atlas (TCGA) were used from studies of CaP (PRAD-TCGA, 498 tumor samples and 52 controls) and CaM (BRCA-TCGA, 1085 tumor samples and 112 controls). Differentially expressed (DE) mRNAs and miRNAs whose log2 of fold change > |±1| and FDR > 0.01 were considered. Global methylation data were considered differentially methylated with β-value > |±0.25| and FDR > 0.01. CaP and CaM miRNA-mRNA data were integrated into the miRWalk 3.0 platform. The mRNA methylation integrations were performed from the correlation between Log2 of fold change and βvalue. Molecular pathway identification had been performed using the Kobas 3.0 tool, target interaction networking was performed on the String platform, and survival curves and genomic analyses on cBioportal and in vivo validations were performed on The Human Protein Atlas. CaP and CaM demonstrated 1,325 genes in common (1,047 down and 278 up). 78 miRNAs were commonly downregulated (7 down and 71 up), in addition to 2,887 methylated regions (556 hypo and 2,331 hyper). Integration between miRNAs and validated mRNAs reported 8 miRNAs regulating 9 mRNAs; and integration between methylation and mRNAs showed 229 down regulated genes with hypermethylation in DNA and 7 up regulated genes with hypomethylation. The molecular pathways were grouped according to functions. Of the methylation regulated genes, 3 PPI interaction clusters were identified, with 12 genes interacting with each other. In Oncoprint genomic alterations were evidenced and we saw their impacts on patient survival, with Angiopoietin-1 (ANGPT1) being most altered in these patients. In silico validation in HPA showed that ANGPT1 downregulated in CaP and CaM tumor tissues. Our data suggest potential genetic and epigenetic mechanisms as CaP and CaM signatures, with ANGPT1 being a good target for further study, we believe that a greater understanding about this gene and its relationship with the evolution of prostate and breast cancers may be an important step towards discoveries of effective therapeutic targets.
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Palavras-chave
Reprodução, Câncer, Multiômicas, TCGA