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

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 importance of the germline landscape in t-MN pathogenesis and support its incorporation into disease classification and risk stratification. Notably, chemotherapy exposure was associated with complex karyotypes and poor prognosis in patients with germline cancer predisposition variants, highlighting a subgroup that may benefit from targeted surveillance and preventive strategies.