DNA methylation is a comprehensive marker for pediatric adrenocortical tumors

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Bueno, Ana Carolina ; da Silva, Rui M. P. ; Stecchini, Monica F. ; Marrero-Gutierrez, Junier ; de Almeida e Silva, Danillo C. ; Cardinalli, Izilda ; Scrideli, Carlos Alberto ; Junqueira, Thais ; Molina, Carlos A. F. ; Ramalho, Fernando Silva ; Tucci, Silvio, Jr. ; Coeli-Lacchini, Fernanda Borchers ; Moreira, Ayrton Custodio ; Ramalho, Leandra N. Z. ; Brandalise, Silvia ; Yunes, Jose Andres ; de Castro, Margaret ; Nicoliello Vencio, Ricardo Zorzetto ; Antonini, Sonir R. R.

• Tipo de documento: Artigo Científico
• Fonte: Endocrine-Related Cancer; v. 29, n. 11, p. 15-pg., 2022-11-01.

Resumo

Children diagnosed with pediatric adrenocortical tumors (pACT) have variable outcomes, and, to date, the disease lacks robust prognostic biomarkers. The prognostic potential of tumor methylation has been demonstrated in several cancers. We aimed to evaluate the pACT methylation profile and its association with disease presentation and survival. In this cross-sectional study, we accessed the DNA methylation (MethylationEPIC Array, Illumina) of 57 primary pACT from Southeastern Brazil and the respective patients' clinicopathological features. We also applied our analysis in an independent 48 pACT methylation dataset. Unsupervised learning whole-methylome analysis showed two groups with distinct methylation signatures: pACT-1 and pACT-2. Compared to pACT-2, pACT-1 tumors were enriched with higher methylation in CpG islands, mainly in gene promoter regions. The topmost hypermethylated gene in these samples was shown to be underexpressed. Patients in the pACT-1 group were older at diagnosis and were more likely to have carcinomas and nonlocalized/advanced and recurrent/metastatic disease. Univariate and bivariate regressions showed that pACT-1 methylation signature confers superior hazard ratio of disease progression and death than known prognostic features. The methylation groups had similar frequencies of germline mutations in the TP53 gene, including the regionally frequent p.R337H. Our analysis replication validated our findings and reproduced those recently described in pACT. We demonstrated the existence of different tumor methylation signatures associated with pACT presentation and clinical evolution, even in the context of germline TP53 mutations. Our data support tumor methylation profiling as a robust and independent prognostic biomarker for pACT and suggest a list of candidate genes for further validation. (AU)

• Processo FAPESP: 20/03835-0 - Aplicação de protocolos padrão de Inteligência Artifical na transcritômica de tumores adrenocorticais pediátricos para estratificação e busca de biomarcadores
• Beneficiário: Junier Marrero Gutiérrez
• Modalidade de apoio: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
• Processo FAPESP: 19/00860-6 - Mecanismos fisiopatológicos e moleculares de tumorigênese: abordagem baseada em plataformas de sequenciamento em escala genômica (NGS - Next-generation sequencing).
• Beneficiário: Ana Carolina Bueno de Queiroz Arruda
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 21/04368-9 - Mecanismos fisiopatológicos e moleculares de tumorigênese: abordagem baseada em plataformas de sequenciamento em escala genômica
• Beneficiário: Danillo Cunha de Almeida e Silva
• Modalidade de apoio: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
• Processo FAPESP: 19/00849-2 - Mecanismos fisiopatológicos e moleculares de tumorigênese: abordagem baseada em plataformas de sequenciamento em escala genômica (NGS - Next-generation sequencing)
• Beneficiário: Rui Milton Patrício da Silva Junior
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/03989-6 - Mecanismos fisiopatológicos e moleculares de tumorigênese: abordagem baseada em plataformas de sequenciamento em escala genômica (NGS - Next-Generation Sequencing)
• Beneficiário: Margaret de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Temático