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Leandro Kasuki Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital
Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital

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Leonardo Vieira Neto Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital
Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital

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Luiz Eduardo A Wildemberg Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital

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Leandro Machado Colli Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital

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Margaret de Castro Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital

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Christina M Takiya Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital

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Mônica R Gadelha Endocrinology Unit, Cell Pathology Laboratory, Endocrinology Unit, Endocrinology Unit, Endocrinology Laboratory, Clementino Fraga Filho University Hospital

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Régia Caroline Peixoto Lira Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil

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Paola Fernanda Fedatto Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil

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David Santos Marco Antonio Department of Research and Development, Fleury Group, Sao Paulo, São Paulo, Brazil

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Letícia Ferro Leal Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil

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Carlos Eduardo Martinelli Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil

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

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Silvio Tucci Department of Surgery, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil

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Luciano Neder Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil

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

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Ana Luiza Seidinger Boldrini Children Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

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Izilda Cardinalli Boldrini Children Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

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Maria José Mastellaro Boldrini Children Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

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José Andres Yunes Boldrini Children Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
State University of Campinas (UNICAMP), CampinasSão Paulo, Brazil

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Silvia Regina Brandalise Boldrini Children Center, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
State University of Campinas (UNICAMP), CampinasSão Paulo, Brazil

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Luiz Gonzaga Tone Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil

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Sonir Roberto Rauber Antonini Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil

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

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Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient’s clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P<0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P=0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth.

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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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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.

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