Análise de variantes genéticas em sítios de splicing de genes do mecanismo de síntese de translesão em pacientes com Neoplasia Mielodisplásica

Abstract

Introduction Myelodysplastic syndrome (MDS) is a hematologic disorder characterized by peripheral blood cytopenias, primarily affecting elderly patients. The disease involves DNA damage and splicing machinery dysfunction. Eight DNA polymerases with translesion activity participate in DNA repair, classified into four families: • Family Y: POLH, POLI, POLK, and REV1 • Family B: POLZ (catalytic subunit REV3L) • Family A: POLQ and POLN • Family X: POLL This study aimed to analyze pathogenic variants in canonical splicing regions of these translesion DNA repair genes in MDS patients. Methods • Patients: 30 MDS cases (17 MDS-EB [excess blasts], 13 MDS-RS [ring sideroblasts]). • Sequencing: Next-generation sequencing (NGS) of coding regions (CDS) with 400x coverage (Illumina). • Variant Analysis: Variants were filtered using SpliceAI (delta score ≥ 0.8). Results Among 30 patients, 20 harbored 11 pathogenic splicing variants: • POLI: Two variants (one acceptor, one donor), predominantly in MDS-EB (80%), with VAF >36% and associated with higher cytogenetic abnormalities. • POLN: Three acceptor variants (two MDS-EB, one MDS-RS). • POLQ: One donor variant in MDS-EB. • REV1: Two acceptor variants in MDS-EB. • POLL & POLM: Variants exclusive to MDS-RS (two acceptor variants in POLL, one donor variant in POLM). Discussion & Conclusion • MDS-EB: POLI variants did not show a clear prognostic impact. • MDS-RS: Variants in POLI were associated with milder disease (higher hemoglobin, platelets >50,000/µL, lower transfusion dependence), suggesting a possible protective effect. Limitations: Small sample size warrants further validation. However, these findings highlight molecular heterogeneity in MDS, with distinct splicing variant profiles between MDS-EB and MDS-RS.