Germline landscape stratification defines distinct molecular and prognostic groups in therapy related myeloid neoplasms

作者：Oriol Calvete, Julia Mestre, Lorea Chaparro‐González, Lucía Ruiz Pérez-Hita, Alba Mesa Tudel, Blanca Xicoy, Lurdes Zamora, Isabel Granada, Mar Mallo, Emili Cid, Estefanía Mancini, Claudia Lozano, Laura Palomo, Pamela Acha, María Julia Montoro, Koji Sasaki, Courtney D. DiNardo, Guillermo Garcia-Manero, Guillermo Montalban-Bravo, Neus Torres Hernández, Marta Santiago Balsera, José Cervera, Gonzalo Maortua, Raquel de Paz, Martí Mascaró, Alfonso García Da Vila, Sara Garcia-Ávila, Juan José Rodríguez‐Sevilla, Leonor Arenillas, Beatríz Bellosillo, Rashmi Kanagal‐Shamanna, Françesc Solé · 发表于：Blood Advances · 年份：2026 · DOI：10.1182/bloodadvances.2026020704 · 研究领域：Acute Myeloid Leukemia Research、Myeloproliferative Neoplasms: Diagnosis and Treatment、Chronic Myeloid Leukemia Treatments

Exposure to chemotherapy and/or radiotherapy increases the risk of therapy-related myeloid neoplasms (t-MN), a heterogeneous group of disorders currently classified by treatment history rather than molecular features. Although germline predisposition has been suggested in approximately 20% of cases, its prevalence and clinical impact remain insufficiently defined. To address this, we analyzed 100 patients with t-MN by integrating clinical characteristics, prior treatment regimens, and genomic profiling. Somatic and germline variants were identified using targeted next-generation sequencing (NGS; n = 33) or whole-exome sequencing (n = 67). Somatic abnormalities, including cytogenetic and/or molecular alterations, were detected in 89.8% of patients. Germline variants were identified in 32.3% of cases, including mutations in cancer predisposition genes (19.8%) and myeloid disease-related genes (14.6%). Patient stratification by germline landscape and gene category defined two prognostic scenarios and three subgroups with distinct clinical outcomes. Patients harboring germline cancer predisposition variants exhibited were enriched for TP53 mutations, complex karyotypes, and had an adverse prognosis. In contrast, patients with germline myeloid-related variants and those without detectable germline variants showed recurrent mutations in TET2, DNMT3A, SF3B1, SRSF2, RUNX1 and ASXL1, were associated with normal karyotypes, and favorable outcomes. These findings underscore the importan...