Vitamin D receptor hypermethylation as a biomarker for pediatric adrenocortical tumors

in European Journal of Endocrinology
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  • 1 Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
  • | 2 Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil
  • | 3 Boldrini Children’s Center, State University of Campinas, Campinas, Sao Paulo, Brazil
  • | 4 Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
  • | 5 Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
  • | 6 Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
  • | 7 Department of Computation and Mathematics, Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of São Paulo, Ribeirao Preto, Sao Paulo, Brazil

Correspondence should be addressed to S R Antonini; Email: antonini@fmrp.usp.br

(L F Leal is now at Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil; Barretos School of Health Sciences, Dr Paulo Prata – FACISB, Sao Paulo, Brazil and is supported by Public Ministry of Labor Campinas (Research, Prevention, and Education of Occupational Cancer))

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Objective

Pediatric adrenocortical tumors (pACT) display complex genomic backgrounds, lacking robust prognostic markers and targeted therapeutic options. Vitamin D3 receptor (VDR) promoter hypermethylation and underexpression were reported in adrenocortical carcinomas from adult patients. In this study, we aimed to investigate VDR expression levels and methylation status in pACT and their clinical and prognostic significance.

Design

Retrospective cross-sectional study enrolling pediatric patients with ACT from two tertiary referral institutions.

Methods

We evaluated clinicopathological features, VDR mRNA (qPCR) and protein (immunohistochemistry) expression, and VDR-wide methylation of ACT samples from 108 pediatric patients. Fourteen pediatric and 32 fetal and postnatal normal adrenals were used as controls.

Results

Unlike in pre- and post-natal normal adrenals, most pACT lacked nuclear VDR expression and had reduced mRNA levels, especially the carcinomas. Unsupervised analysis of VDR methylation data revealed two groups of pACT with distinct disease features and outcomes. Tumors with high VDR methylation presented lower mRNA levels, and the respective patients presented advanced disease and reduced disease-free and overall survival.

Conclusions

VDR has a role in normal adrenocortical development and homeostasis, which is impaired during tumorigenesis. VDR hypermethylation and underexpression may be both predictive and prognostic biomarkers for pACT.

Supplementary Materials

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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