ASH 2023: Predicting DDX41-Mutant MDS Outcomes Needs a Risk Scoring System

Hypomorphic DDX41 mutations can lead to a higher chance of developing a type of blood cancer called myeloid neoplasia (MN), especially myelodysplastic syndrome (MDS), later in life. A recent study found that these gene mutations are present in up to 5% of MDS cases and account for about 80% of known genetic predisposition to myeloid neoplasia. People with DDX41 mutations have around a 50% risk of developing myeloid neoplasia during their lifetime. The risk increases when a secondary mutation occurs in the opposite gene (commonly p.R525H), which affects males more. Existing classification systems may not accurately predict the risk for DDX41-mutant MDS, as these mutations create a unique type of disease that current tools may need to understand fully. The impact of secondary DDX41 mutations on the progression of the disease has yet to be thoroughly studied.

At ASH 2023, we had the privilege of interviewing Carmelo Gurnari from the Cleveland Clinic/University of Rome Tor Vergata. You can watch the video below or continue reading to learn more about this exciting research. 

In the abstract, he presented, “Outcome Prediction in DDX41-Mutant Myelodysplastic Syndromes Is Not Possible with General Disease Schemes and Requires a Dedicated Risk Scoring System”,  where they demonstrated that current schemes generally used for the disease prognosis are not able to capture the invariant features of this particular MDS subset. They found that the specific genomic constellation typical for DDX41 mutation, in particular the presence of a truncating mutation or the acquisition of a second somatic lesion on the contralateral alil of the same gene, the one that primarily impacts disease outcome in terms of overall survival and leukemia progression. 

The study also found that a transplant can nullify the negative impact on overall survival, as Dr. Gurnari mentions. 
“This is the first time germline configurations are taken into account in MDS risk scores, and I hope tha” concludes Dr. Gurnari. 

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