Germline Variants Define Prognostic Subgroups in Therapy-Related Myeloid Neoplasms
核心洞察
A study of 100 patients with therapy-related myeloid neoplasms (搜索) found germline variants in 32.3% of cases, with somatic variants present in 89.8%.
Patients with germline cancer predisposition variants showed higher rates of TP53 (搜索) mutations, complex karyotypes, and poor prognosis, while those with myeloid disease-related or no germline variants had better outcomes.
Researchers concluded that incorporating germline genetic testing into disease classification and risk stratification could guide personalized treatment and identify families needing genetic counseling or surveillance.
Inherited genetic variants play a significant role in therapy-related myeloid neoplasms (搜索) and can help identify patients with distinct levels of risk, according to research published in Blood Advances. The study, led by senior group leader Francesc Solé, PhD, at the Josep Carreras Leukemia Research Institute (搜索), found that germline genetic testing could improve disease classification, guide clinical decisions, and identify individuals and families who may benefit from genetic counseling, closer monitoring, or preventive strategies before or after cancer treatment.
"These findings underscore the importance of the germline landscape in therapy-related myeloid neoplasms (搜索) pathogenesis and support its incorporation into disease classification and risk stratification," the study authors concluded.
Study Design and Genomic Profiling
Researchers examined the clinical characteristics, prior treatment regimens, and genomic profile of 100 patients with therapy-related myeloid neoplasms (搜索) to characterize the prevalence and clinical impact of the disease. Using targeted next-generation sequencing and whole-exome sequencing, they identified somatic and germline variants.
Somatic variants were found in 89.8% of patients, while germline variants were detected in 32.3%. The most common germline variants were mutations in cancer predisposition genes (19.8%) and myeloid disease–related genes (14.6%).
Prognostic Subgroups and Clinical Outcomes
Patients were stratified according to germline landscape and gene category into two prognostic scenarios and three subgroups, each with distinct clinical outcomes.
Those with germline cancer predisposition variants were more likely to have TP53 (搜索) mutations, complex karyotypes, and a poor prognosis. In contrast, patients with germline myeloid disease–related gene variants and those without detectable germline variants were more likely to have a better prognosis, along with recurrent mutations in TET2 (搜索), DNMT3A (搜索), SF3B1 (搜索), SRSF2 (搜索), RUNX1, and ASXL1 (搜索), and normal karyotypes.
The study authors noted that exposure to chemotherapy was associated with complex karyotypes and poor prognoses in patients with germline cancer predisposition variants, suggesting that this patient subgroup could benefit from targeted surveillance and preventive strategies.
Clinical Implications
"Our findings show that inherited genetics play an important role in therapy-related myeloid neoplasms (搜索) and can help identify patients with different levels of risk. Including germline genetic testing in the evaluation of these patients could improve disease classification, guide clinical decisions, and help identify individuals and families who may benefit from genetic counselling, closer monitoring, or preventive strategies before or after cancer treatment," said co-first study author Julia Mestre, a PhD student at the Josep Carreras Leukemia Research Institute (搜索).
The results highlight the growing recognition of germline predisposition as a distinct entity within hematologic malignancies, where inherited variants in genes such as DDX41 (搜索), RUNX1, GATA2 (搜索), ANKRD26 (搜索), and SAMD9 (搜索)/SAMD9L (搜索) are increasingly identified through next-generation sequencing. A key paradigm shift is the understanding that germline variants alone are sometimes insufficient to drive disease, requiring additional somatic events, with this germline–somatic interplay shaping phenotype, progression, and the interpretation of variants of uncertain significance.