8485 Transcriptome Profiling Of Pediatric Adrenocortical Tumors (pACT) According To Disease Presentation Reinforces Prognostic Markers And Reveals A Lincrna As A Potential Therapeutic Target
Authors: Arruda A B , da Silva-Júnior R P , Stecchini M F , Marrero-Gutiérrez J , Cardinalli I , Junqueira T , Scrideli C , Molina C A , Silvio T , Silvio T , Coeli-Lacchini F , Ramalho F S , Ramalho L , Moreira A C , Brandalise S , Yunes A , Vêncio R Z , Castro M De , Antonini S R Rauber 
Published: October 2024

Abstract
Disclosure: A.B. Arruda: None. R.P. da Silva-Júnior: None. M.F. Stecchini: None. J. Marrero-Gutiérrez: None. I. Cardinalli: None. T. Junqueira: None. C. Scrideli: None. C.A. Molina: None. T. Silvio: None. T. Silvio: None. F. Coeli-Lacchini: None. F.S. Ramalho: None. L. Ramalho: None. A.C. Moreira: None. S. Brandalise: None. A. Yunes: None. R.Z. Vêncio: None. M. De Castro: None. S.R. Rauber Antonini: None.
Aim: To uncover a feasible prognostic tumor expression signature and potential new therapeutic targets for pACT. Methods: 53 children with ACT were included (70% girls, median age 1.7y). Patients’ progression-free (PFS) and overall survival (OS) were calculated (Kaplan-Meier curves and log-rank). Tumor methylation signatures were analyzed. Tumor RNAseq was performed and the differentially expressed genes (DEGs) between tumors presenting with favorable and unfavorable disease progression-associated features were selected. DEG-sets pathway over-representation analysis (ORA) was performed. Prognostic tumor expression signature was recognized by overlapping DEGs in the prognostic features’ categories and identifying the intersecting ones. DEGs of interest were validated by qPCR. Results: Median patients follow-up was 5.2y (5y-PFS: 91% and 5y-OS: 91%). Age at diagnosis, IPACTR’s disease stage, Wieneke’s histopathological diagnosis and methylation signature were associated with PFS and/or OS. Children presenting with stages III and IV (n=12, 23%) vs I and II (n=41, 77%) had reduced OS (5y: 80 vs 94%; p=0.03). OS was lower in patients with carcinomas (5y: 72%) and those with uncertain malignancy (UM; 5y: 92%) vs adenomas (100%; p&lt;0.05). Children with pACT-1 (n=5, 9%) vs pACT-2 (n=38, 72%) methylation signature had reduced PFS (5y: 25 vs 96%) and OS (5y: 20 vs 100%) (both p&lt;0.0001). The transcriptome size was of 16.201 eligible transcripts. No over-represented pathway was found regarding age and disease stage at diagnosis. Adenoma vs carcinomas and vs UM tumors differential transcriptomes were 4.4% and 1.5%, respectively, and over-represented down-regulation of energy metabolism and hypoxia, and up-regulation of immunity/inflammation, PI3K-Akt, JAK-STAT, and pathways in cancer. pACT methylation signatures had 2.5% differential transcriptome. Tumors with methylation signature associated with better outcomes (pACT-2) presented down-regulation of energy metabolism, extracellular matrix-receptor interaction, and hypoxia, and up-regulation of NK-cell mediated cytotoxicity, and TGF-beta receptor pathways. Remarkably, one single transcript intersected within all the comparisons: LINC01234, a long intergenic non-coding RNA (lincRNA). LINC01234 upregulation was associated with reduced PFS (p=0.04), OS (p=0.007), older age (&gt;4y; p=0.01) and pACT-1 methylation signature (p=0.04). These findings were validated by qPCR. Conclusion: pACT transcriptome aligns clinical, histopathological and methylation signature prognostic features. Deregulation of energy metabolism and immune/inflammatory response genes were associated with lower survival. LINC01234 is a new prognostic marker for patients with pACT and a potential new target for precision therapy.
Presentation: 6/3/2024