Germ line landscape stratification defines distinct molecular and prognostic groups in therapy-related myeloid neoplasms

Abstract Exposure to chemotherapy (CT) 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 germ line predisposition has been suggested in ∼20% of patients, 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 germ line variants were identified using targeted next-generation sequencing (n = 33) or whole-exome sequencing (n = 67). Somatic abnormalities, including cytogenetic and/or molecular alterations, were detected in 89.8% of patients. Germ line variants were identified in 32.3% of patients, including mutations in cancer predisposition genes (19.8%) and myeloid disease–related genes (14.6%). Patient stratification by germ line landscape and gene category defined 2 prognostic scenarios and 3 subgroups with distinct clinical outcomes. Patients harboring germ line cancer predisposition variants were enriched for TP53 mutations and complex karyotypes and had an adverse prognosis. In contrast, patients with germ line myeloid-related variants and those without detectable germ line variants exhibited recurrent mutations in TET2, DNMT3A, SF3B1, SRSF2, RUNX1, and ASXL1, were associated with normal karyotypes, and had favorable outcomes. These findings underscore the importance of the germ line landscape in t-MN pathogenesis and support its incorporation into disease classification and risk stratification. Notably, CT exposure was associated with complex karyotypes and poor prognosis in patients with germ line cancer predisposition variants, highlighting a subgroup that may benefit from targeted surveillance and preventive strategies.