Multi-hit STAG2 mutations define a high-risk subset of MDS and reveal convergent evolutionary targeting of cohesin
STAG2 is the most frequently mutated cohesin gene in myeloid neoplasms, yet the significance of multiple mutations within this X-linked tumor suppressor remains unknown. We analyzed a cohort of 1,967 adult patients with myeloid neoplasms and identified 233 cases (12%) harboring STAG2 mutations, including 38 cases (16%) with multiple STAG2 hits. Patients with multi-hit STAG2 mutations exhibited…
A recent study examines the impact of multiple mutations in the STAG2 gene, a cohesin suppressor implicated in myeloid neoplasms. The analysis of 1,967 adult patients revealed that 12% had STAG2 mutations, with 16% experiencing multiple hits. These multi-hit cases exhibited more severe multilineage dysplasia and had a poorer prognosis, particularly among those with myelodysplastic syndromes (MDS).
Long-read sequencing in representative cases revealed that distinct truncating STAG2 mutations emerged independently, rather than through a stepwise inactivation process. Furthermore, the variant allele frequency patterns suggested that STAG2 was targeted repeatedly in related clonal populations, indicating convergent evolutionary targeting.
Overall, the findings suggest that multi-hit STAG2 mutations are the result of convergent evolution and represent a biologically distinct, adverse-risk subset of MDS.
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