Multi-hit STAG2 mutations define a high-risk subset of MDS and reveal convergent evolutionary targeting of cohesin
- 1Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY
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.
Related
- Fc-Dependent Targeting of the GAS6-MERTK Axis With Monoclonal and Bispecific Antibodies Overcomes Drug Resistance Across EGFR Mutations in Exons 19, 20, and 21.
- Targeting KRAS Codon 13 Mutations Using Direct Combination Approaches in Non–Small Cell Lung Cancer
- STAG2-truncating variants reveal a mosaic STAG2 inactivation pattern and compensatory mechanisms involving cohesin complex remodeling
- Immune-metabolic-redox ecosystems define spatially organized tumor states in head and neck squamous cell carcinoma.
- Disulfidptosis-related genes and long non-coding RNAs define a prognostic model for liver cancer
BibTeX
@misc{udoh2026multihit,
title = {{Multi-hit STAG2 mutations define a high-risk subset of MDS and reveal convergent evolutionary targeting of cohesin}},
author = {E.-o. B. Udoh and Y. Chen and M. D'Addona and E. Stewart and R. Deng and F. de Almeida Sartori and S. Unlu and Z. Brady and R. Zhu and X. Cheng and V. Scoca and J. J. Xu and S. Doulatov and K. Theil and D. Bosler and V. Visconte and J. P. Maciejewski and A. D. Viny},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.02.749005},
url = {https://www.biorxiv.org/content/10.64898/2026.09.02.749005v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Multi-hit STAG2 mutations define a high-risk subset of MDS and reveal convergent evolutionary targeting of cohesin
AU - E.-o. B. Udoh
AU - Y. Chen
AU - M. D'Addona
AU - E. Stewart
AU - R. Deng
AU - F. de Almeida Sartori
AU - S. Unlu
AU - Z. Brady
AU - R. Zhu
AU - X. Cheng
AU - V. Scoca
AU - J. J. Xu
AU - S. Doulatov
AU - K. Theil
AU - D. Bosler
AU - V. Visconte
AU - J. P. Maciejewski
AU - A. D. Viny
PY - 2026
DA - 2026/09/02
PB - bioRxiv
DO - 10.64898/2026.09.02.749005
UR - https://www.biorxiv.org/content/10.64898/2026.09.02.749005v1
AB - 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.
ER -