IDENTIFICATION OF SINGLE NUCLEOTIDE VARIANTS AND FUSION GENES THROUGH TRANSCRIPTOMICS OF PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS FROM A MULTICENTER CLINICAL STUDY IN ARGENTINA

RUIZ, MARÍA SOL; RICCHERI, CECILIA; COTIGNOLA, JAVIER; AVENDAÑO, DANIEL; GUERON, GERALDINE; ABBATE, MARÍA MERCEDES; VAZQUEZ, ELBA

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

SAIC - SAFIS - SAI

Patientsdiagnosed with Acute Lymphoblastic Leukemia (ALL) are stratified into riskgroups based on biochemical, cytogenetic and molecular signatures. Whileconsiderable progress has been made on treatment efficacy and survival rates,relapse is the most important cause for treatment failure and occurs in about15-30% of patients. In approximately one-third of B-ALL patients, majorpathogenic molecular abnormalities have yet to be identified. Aims: to characterize molecular profilesassociated with disease outcome and improve molecular classification of ALLpatients from Argentina. Methods: westudied single nucleotide variants and fusion genes in 39 pediatric ALLpatients that are part of a national multicenter clinical protocol (ALL ICGATLA 2010), through transcriptome sequencing of bone marrow samples atdiagnosis. RNAmut software was used to evaluate SNVs/InDels in 114 selectedgenes and 79 selected fusion genes in RNA-seq data. Discovery of fusion geneswas complemented with STAR-Fusion software. Variants were analyzed andfiltered based on an in-house pipeline. Variants were assessed in silico through Variant EffectPredictor, OncoKB, Varsite, ProteinPaint and COSMIC-3D. Confirmation wasperformed by RT-PCR and Sanger sequencing. Results:We found a total of 9,594 variants. After annotation and filtering, 20SNVs/InDels were identified in 11/34 patients (32.3%). Variants that had notbeen previously described in ALL were found in CREBBP, CSF3R, ETV6, TP53, ATM and DUX4. The group of patients harboringpoint mutations had significantly lower relapse-free survival (p<0.05). Fusiongenes previously reported in ALL were found in 8/34 patients (23.5%).Combination of RNAmut and STAR-Fusion increased sensitivity of fusion genedetection. Conclusions: This is thefirst comprehensive molecular characterization of pediatric ALL patients inArgentina. Transcriptomic sequencing allowed the simultaneous identification ofmultiple molecular features of clinical relevance