Identifying germline genetic variants in patients with therapy-related myeloid neoplasms revealed distinct molecular and prognostic subgroups with distinct outcomes, according to research findings published in Blood Advances. The findings could help to guide physicians in determining which patients need more personalized risk assessment and treatments.
"Our findings show that inherited genetics play an important role in therapy-related myeloid neoplasms 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. The research was led by senior group leader Francesc Solé, PhD.
Study Methods and Key Findings
Researchers looked at the clinical characteristics, prior treatment regimens, and genomic profile of 100 patients with therapy-related myeloid neoplasms to characterize and learn more about the prevalence and clinical impact of the disease.
They used targeted next-generation sequencing and whole-exome sequencing to find somatic and germline variants, with somatic variants found in 89.8% of patients and germline variants in 32.3%. The most common germline variants were mutations in cancer predisposition genes (19.8%) and myeloid disease–related genes (14.6%).
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 mutations, complex karyotypes, and have a poor prognosis. On the other hand, those with germline myeloid disease–related gene variants and patients without detectable germline variants were more likely to have a better prognosis as well as recurrent mutations in TET2, DNMT3A, SF3B1, SRSF2, RUNX1, and ASXL1, and normal karyotypes.
The study authors added that exposure to chemotherapy was associated with complex karyotypes and poor prognoses in patients with germline cancer predisposition variants, and suggested that this patient subgroup could benefit from targeted surveillance and preventive strategies.
"These findings underscore the importance of the germline landscape in therapy-related myeloid neoplasms pathogenesis and support its incorporation into disease classification and risk stratification," the study authors concluded.
DISCLOSURES: The study was supported by the Instituto de Salud Carlos III and a Joan Oró Predoctoral Fellowship from AGAUR, Generalitat de Catalunya. For full disclosures of the study authors, visit ashpublications.org.
