ESPE2023 Poster Category 1 Adrenals and HPA Axis (40 abstracts)
Transcriptome profiling evaluation of pediatric adrenocortical tumors (pACT) reveals a favorable-prognosis transcription signature and potential therapeutic targets.
Ana Carolina Bueno 1 , Rui Milton P da Silva Jr 1 , Mônica F Stecchini 1 , Junier Marrero-Gutiérrez 1 , Izilda A Cardinalli 2 , Tais 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 , Jose A Yunes 2 , Ricardo ZN Vêncio 3 , Margaret de Castro 1 & Sonir R Antonini 1
1Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil. 2Boldrini Children´s Center, Campinas, Brazil. 3Philosophy, Sciences and Letters at Ribeirao Preto, Ribeirao Preto, Brazil
Aim: To uncover a feasible tumor expression prognostic signature and potential therapeutic targets for children with pACT.
Methods: Tumor RNAseq from 53 pACT children (70% girls, median age: 1.7yrs) was performed (Illumina). Using a robust, state-of-the-art, differential gene expression analysis pipeline, differentially expressed genes (DEGs: adjusted P<0.05 and |log2 fold-change|>1) were identified (DESeq2). We investigated the DEGs between known favorable disease-progression associated features at diagnosis: age<4yrs, localized disease (IPACTR stages I+II), diagnosis of adenomas (Wieneke score <2), and pACT-2 tumor methylation signature, and which of these DEGs overlapped within these features. DEG-sets enrichment of gene ontology biological process and pathway over-representation were analyzed (P<0.005). Patients’ progression-free (PFS) and overall survival (OS) were calculated (Kaplan-Meier curves and log-rank).
Results: Favorable progression was observed in patients diagnosed <4yrs of age [n=45 (85%), 5yr-PFS=97% and 5yr-OS=100%, both P<0.0001], with localized disease [n=41 (73%), 5yr-OS=94%, P=0.03], with adenomas [n=24 (45%) 5yr-PFS and 5y-OS both 100%, P=0.04 and P=0.03, respectively], and with pACT-2 methylation signature [n=38 (88%), 5yr-PFS=96% and 5yr-OS=100%, both P<0.0001]. The down-regulated DEG-set (down_DEG-set, n=79) from younger children’s pACT was enriched for calcium-ion regulation of exocytosis and sphingolipid biosynthesis, and the up_DEG-set (n=15) for immune and inflammatory response. Localized disease down_DEG-set (n=48) was involved in immune cell differentiation, and the up_DEG-set (n=7) in MAPK cascade, response to metal-ion, carbohydrate metabolism, and negative regulation of hippo signaling. The down_DEG-set from adenomas (n=22) over-represented fructose and mannose metabolism, glycolysis/gluconeogenesis, and mitophagy; and the up_DEG-set (n=115) over-represented immune and inflammatory response, mesenchymal stem cell differentiation, negative regulation of epithelial cell apoptotic process, PI3K-Akt and JAK-STAT. The pACT-2 down_DEG-set (n=202) was enriched for fructose, mannose, and pentose phosphate pathways, glycolysis/gluconeogenesis, extracellular matrix-receptor interaction, and HIF-1 signaling; and the up_DEG-set (n=202) for NK-cell mediated cytotoxicity, and TGF-beta receptor pathways. Overlapping the DEGs within all evaluated favorable features revealed the differential expression (down-regulation) of one single transcript, which was also up-regulated in the carcinomas: a long intergenic non-coding RNA (lincRNA), not-yet described in adrenocortical tumorigeneses but involved in the regulation of multiple tumors and Wnt signaling pathway, whose increased expression was associated with reduced PFS (P=0.04) and OS (P=0.007) of our patients.
Conclusion: Our data reveal that tumor deregulation of energy metabolism and immune/inflammatory response mainly compromise the prognosis of children with ACT, and uncovers a lincRNA as a novel potential target for precision therapy and precise prognostic management of children with ACT.
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