Multi-hit STAG2 mutations define a high-risk subset of MDS and reveal convergent evolutionary targeting of cohesin
Udoh, E.-o. B.; Chen, Y.; D'Addona, M.; Stewart, E.; Deng, R.; de Almeida Sartori, F.; Unlu, S.; Brady, Z.; Zhu, R.; Cheng, X.; Scoca, V.; Xu, J. J.; Doulatov, S.; Theil, K.; Bosler, D.; Visconte, V.; Maciejewski, J. P.; Viny, A. D.
Show abstract
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 increased multilineage dysplasia compared with single-hit cases and experienced inferior overall survival, an effect driven primarily by patients with myelodysplastic syndromes (MDS). To investigate the molecular basis of recurrent STAG2 acquisition, we performed long-read sequencing in representative cases with phaseable STAG2 mutations. In the informative case examined, distinct truncating STAG2 mutations did not co-occur on the same DNA molecule, supporting independent acquisition rather than stepwise allelic inactivation. Cohort-level variant allele frequency patterns were consistent with recurrent evolutionary targeting of STAG2 across related clonal populations. Together, these findings support a model in which multi-hit STAG2 mutations arise through convergent evolution and define a biologically distinct, adverse-risk subset of MDS.
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