Prognostic Score for Myelodysplastic Syndromes Based on Molecular Evolution.

作者：I. Civettini, F. Malighetti, M. Villa, Valentina Crippa, A. Aroldi, F. Cavalca, Alex Graudenzi, L. Lanino, G. Maggioni, T. Haferlach, P. Fenaux, U. Platzbecker, María Díez-Campelo, L. Borin, M. Fumagalli, Arianna Zappaterra, B. Manghisi, N. Al Ali, D. Sallman, E. Padron, Zhuoer Xie, O. Chan, A. Zeidan, L. Mologni, R. Piazza, R. Komrokji, M. G. Della Porta, C. Gambacorti-Passerini, D. Ramazzotti · 发表于：NEJM Evidence · 年份：2026 · DOI：10.1056/evidoa2500124 · 被引用次数：1 · 研究领域：Medicine

BACKGROUND Myelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by multistep molecular evolution and a variable risk of leukemic transformation. Given this prognostic heterogeneity, accurate risk stratification is essential for clinical decision-making. We developed ProgEvo, a proprietary framework that infers molecular evolutionary trajectories and integrates them with clinical data to improve prognostic accuracy. METHODS ProgEvo was trained on 2519 patients in cBioPortal (https://www.cbioportal.org) and validated using two external cohorts: Genomed4All (2043 patients) and a Moffitt Cancer Center (MCC) cohort (2157 patients). Directional evolutionary routes were inferred and selected for prognostic modeling if they were consistently associated with leukemia-free survival. A multivariable feature selection strategy was applied to integrate evolution-consistent variables into the existing IPSS-M model. RESULTS ProgEvo identified 1765 gene co-occurrences aggregated into 45 directional evolutionary routes. Of these, 18 were validated in the Genomed4All cohort. Five evolution-informed variables, two directional routes (Additional Sex Combs-Like 1 [ASXL1]→KRAS Proto-Oncogene [KRAS] and Serine and Arginine-Rich Splicing Factor 2 [SRSF2]→NRAS Proto-Oncogene [NRAS]), one co-occurrence (NRAS/RUNX Family Transcription Factor 1 [RUNX1]), and two early mutations (ATRX [ATRX Chromatin Remodeler] and Janus Kinase 2 [JAK2]) were integrated into IPSS-M to ...