Inherited genetic variants help identify patients at higher risk of aggressive therapy-related blood cancers

Certain patients experience aggressive blood cancers years after chemotherapy or radiotherapy for previous cancers. Though traditionally classified based on treatment history, clinical courses of these therapy-related myeloid neoplasms (t-MN) differ significantly among individuals. A study led by researchers from the Josep Carreras Leukaemia Research Institute and published in Blood Advances now reveals that genetic variants inherited from birth can explain these variations in disease behavior.

Analyzing genetic and clinical data of 100 t-MN patients, the researchers found nearly one-third carried inherited genetic variants associated with cancer predisposition or blood disorders. Based on these inherited variants, the patients were grouped into three molecular subgroups with unique biological features and clinical outcomes.

Those with inherited variants in cancer predisposition genes were more likely to exhibit extensive chromosome abnormalities and TP53 gene alterations, which are linked to poorer prognosis. In contrast, those with inherited variants tied to blood disorders or without detectable inherited variants generally had different molecular changes and more favorable outcomes.

The study suggests inherited genetics plays a larger role in t-MN than previously thought, rather than relying solely on prior chemotherapy or radiotherapy information. Incorporating germline genetic data could offer a more precise method for classifying patients and estimating their risk. Dr. Julia Mestre, a researcher and first author of the study, emphasized that including germline genetic testing in evaluating these patients could enhance disease classification, guide clinical decisions, and identify individuals and families who might benefit from genetic counseling, closer monitoring, or preventive strategies before or after cancer treatment.

The research also highlighted that chemotherapy exposure was associated with poorer outcomes in patients carrying inherited cancer-predisposition variants. These patients frequently presented with complex chromosomal abnormalities and TP53 alterations, which likely explain why some individuals develop particularly aggressive forms of therapy-related disease.

While further studies are required before these findings are adopted into standard clinical practice, the work offers a framework for improving the management of patients with therapy-related myeloid neoplasms. Integrating inherited genetic testing into clinical evaluation could facilitate more personalized treatment decisions, enhance follow-up strategies, and identify patients and relatives who might benefit from genetic counseling and surveillance.