ESPE2022 Free Communications Adrenals and HPA Axis (6 abstracts)
Transcriptome profiling of adrenocortical tumors from children with unfavorable disease presentation.
Ana C Bueno 1 , Rui M P da Silva Jr 1 , Mônica F Stecchini 1 , Izilda A Cardinalli 2 , Thais Junqueira 2 , Carlos A Scrideli 1 , Carlos AF Molina 1 , Silvio Tucci 1 , Fernanda B Coeli-Lacchini 1 , Ayrton C Moreira 1 , Leandra NZ Ramalho 1 , Silvia R Brandalise 2 , José A Yunes 2 , Ricardo ZN Vêncio 3 , Margaret de Castro 1 & Sonir R Antonini 1
1Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil; 2Boldrini Children's Center, Campinas, Brazil; 3Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of São Paulo, Ribeirao Preto, Brazil
Children diagnosed with adrenocortical tumors (ACT) have variable prognosis depending on disease presentation at diagnosis. Available therapeutic options render excellent outcome for a subset of patients, but limited improvement in the survival of those diagnosed with non-localized/advanced disease. ACT DNA methylation was recently demonstrated to be a robust and independent prognostic biomarker. Aiming to identify potential therapeutic targets for these children, we compared the transcriptomes of ACT presenting with favorable and unfavorable-disease features. Total RNA was extracted from 53 fresh-frozen, microdissected samples. RNA-Seq was performed according to Illumina’s protocol. FASTQ files were merged and aligned to GRCh37 (STAR). Read counts were normalized by each library’s size using the Counts Per Million method, processed and analyzed (HTSeq). Genes with adjusted P-value <0.05 and log2 fold change >1 or <-1 were considered differentially expressed (DESeq2). Pathway enrichment analysis was preformed using Enrichr and Panther 2016. The study included 37 girls (70%, female-to-male ratio 2.3:1), with median age of 1.7 years (range: 0.2-16.6). Five-year overall survival (5y-OS) was 91%. OS was reduced in patients diagnosed after 4 years [n=8 (15%): 7 (13%) between 4-12 and 1 (2%) >13 years, 5y-OS=50%, P<0.0001), with advanced/non-localized disease (IPACTR stages III and IV; n=12 (27%), 5y-OS=80%, P=0.03) or carcinomas (Wieneke score ≥4; n=13 (24%), 5y-OS=72%, P=0.019), and in those whose tumors had pACT-1 methylation signature (n=5 (9%), 5y-OS=20%, P<0.0001). Compared with younger patients, ACT from older patients exhibited underexpression of genes (n=15) associated with immune response and tumorigenesis, and overexpression of genes (n=79) involved in calcium reabsorption and CYPP450 metabolism. ACT from advanced/non-localized disease had underexpression of genes (n=48) associated with carbohydrate metabolism, interleukin signaling, cadherin and Wnt pathway, and overexpression of genes (n=7) associated with immune response, tumorigenesis and B cell activation. Compared with adenomas, carcinomas exhibited underexpression of genes (n=210) involved with immune response, B cell activation, metabolism and the Hedgehog pathway, whereas among overexpressed genes (n=228), metabolic, integrin and cell cycle signaling pathways stood-out. Compared with pACT-2 methylation signature, pACT-1 tumors were underexpressed for genes (n=210) associated with TGF-B, PI3K and insulin/IGF signaling, and overexpressed for genes (n=210) involved in carbohydrate metabolism, integrin, P53 and Wnt signaling pathways. Our data strengthens the importance of pathways known to be deregulated in ACT and reveals novel targets to be investigated in order to develop precision therapeutic options for children diagnosed with unfavorable disease.
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