DNA methylation is a comprehensive marker for pediatric adrenocortical tumors

Author(s):Show less -

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.

• Document type: Journal article
• Source: Endocrine-Related Cancer; v. 29, n. 11, p. 15-pg., 2022-11-01.

Abstract

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)

• FAPESP's process: 20/03835-0 - Application of standard Artificial Intelligence protocols on transcriptome of pediatric adrenocortical tumors for stratification and search for biomarkers
• Grantee: Junier Marrero Gutiérrez
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 19/00860-6 - Uncovering pathophysiological and molecular mechanisms involvedin tumorigenesis by platforms for next-generation sequencing (NGS)
• Grantee: Ana Carolina Bueno de Queiroz Arruda
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/04368-9 - Physiopathological and molecular mechanisms of tumorigenesis: Genomic scale sequencing platform based approach (NGS - Next-generation sequencing)
• Grantee: Danillo Cunha de Almeida e Silva
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 19/00849-2 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS)
• Grantee: Rui Milton Patrício da Silva Junior
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/03989-6 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS)
• Grantee: Margaret de Castro
• Support Opportunities: Research Projects - Thematic Grants