Multi-hit STAG2 mutations define a high-risk subset of MDS and reveal convergent evolutionary targeting of cohesin

Authors:
Preprint
Publisher website
Google Scholar
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. Key points: Multi-hit STAG2 mutations identify a high-risk subset of MDS characterized by increased multilineage dysplasia and inferior survival. Long-read sequencing supports convergent evolutionary acquisition of STAG2 mutations rather than stepwise allelic inactivation.
Funding Information
  • Damon Runyon Cancer Research Foundation (Damon-Runyon-Doris Duke Clinical Investigator (CI-120-22))
  • Doris Duke Charitable Foundation (Clinician Scientist Development Award)
  • NIH/NCI Cancer Center Support Grant (P30CA012696)
  • NCATS Clinical and Translational Science Awards (CTSA) Grant (UL1TR001873)
  • Genomics and High Throughput Screening Shared Resource

This publication has 36 references indexed in Scilit: