DNA methylation is a comprehensive marker for pediatric adrenocortical tumors

in Endocrine-Related Cancer
Authors:
Ana Carolina Bueno Department of Pediatrics Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Rui M P da Silva Department of Internal Medicine Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Mônica F Stecchini Department of Pediatrics Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Junier Marrero-Gutiérrez Department of Pediatrics Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Danillo C de Almeida e Silva Department of Internal Medicine Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
Department of Computation and Mathematics, Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Izilda Cardinalli Boldrini Children’s Center, State University of Campinas, Campinas, Sao Paulo, Brazil

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Carlos Alberto Scrideli Department of Pediatrics Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Thais Junqueira Boldrini Children’s Center, State University of Campinas, Campinas, Sao Paulo, Brazil

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Carlos A F Molina Department of Surgery and Anatomy Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Fernando Silva Ramalho Department of Pathology Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Silvio Tucci Jr Department of Surgery and Anatomy Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Fernanda Borchers Coeli-Lacchini Department of Internal Medicine Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Ayrton Custodio Moreira Department of Internal Medicine Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Leandra N Z Ramalho Department of Pathology Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Silvia Brandalise Boldrini Children’s Center, State University of Campinas, Campinas, Sao Paulo, Brazil

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José Andres Yunes Boldrini Children’s Center, State University of Campinas, Campinas, Sao Paulo, Brazil

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Margaret de Castro Department of Internal Medicine Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Ricardo Zorzetto Nicoliello Vêncio Department of Computation and Mathematics, Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Sonir R R Antonini Department of Pediatrics Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

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Correspondence should be addressed to S R R Antonini: antonini@fmrp.usp.br
DOI:
https://doi.org/10.1530/ERC-22-0145
Volume/Issue:
Volume 29: Issue 11
Article Type:
Research Article
Page Range:
599–613
Online Publication Date:
30 Sep 2022
Copyright:
© the author(s) 2022
Restricted access
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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.

Supplementary Materials

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© the author(s) 2022
Page(s):
15
Received Date:
29 Jul 2022
Accepted Date:
30 Aug 2022
Print Publication Date:
01 Nov 2022
Online Publication Date:
30 Sep 2022
Keywords:
pediatric adrenocortical tumor; DNA methylation; survival; prognosis

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