STAG2

Overview

STAG2 encodes a subunit of the cohesin complex essential for sister chromatid cohesion and chromosome segregation. Somatic loss-of-function mutations in STAG2 are among the most recurrent alterations in myelodysplastic syndromes (MDS) and are strongly associated with megakaryocyte nuclear separation defects — a morphologic feature that may serve as a clinical surrogate for STAG2 mutation status.

Alterations observed in the corpus

  • Somatic loss-of-function STAG2 mutations are the strongest genetic predictor of separated megakaryocyte nuclei in MDS bone marrow biopsies: 69% of STAG2-mutant cases vs 22% of unmutated (P<0.0001), abnormal myeloid nuclear segmentation (58% vs 19%; P<0.0001), and hypogranulation (74% vs 21%; P<0.0001) PMID:21909114
  • STAG2 is a cohesin-complex gene recurrently mutated in AML (13% combined cohesin prevalence with SMC1A, SMC3, and RAD21) PMID:23634996
  • Predominantly truncating somatic mutations (frameshift indels, nonsense, splice-site) in 11/99 (11%) TCC tumors; additional 5/99 with genomic deletions; promoter hypermethylation in 23% (7/30); alterations associated with worse overall survival and increased aneuploidy; newly identified high-frequency bladder cancer driver PMID:24121792
  • Predominantly inactivating mutations in 11% of bladder urothelial carcinoma (BLCA) tumors; X-linked cohesin complex component identified as a significantly mutated gene in TCGA bladder cancer cohort PMID:24476821
  • Mutations present in high-grade urothelial carcinoma (MSK-IMPACT, n=109) but not associated with recurrence-free or cancer-specific survival outcomes in this cohort. PMID:25092538
  • STAG2 loss-of-function mutations (nonsense, frameshift, splice-site, exon-22 duplication) in 17% of Ewing sarcoma WGS cohort and 13.2% of 299-patient combined cohort; mutually exclusive with CDKN2A deletion; co-occurs with TP53 mutation; can be subclonal at diagnosis and expand at relapse PMID:25223734
  • Significant association with T stage in UTUC (upper tract urothelial carcinoma) cohort (n=83); detected by 300-gene MSK-IMPACT targeted panel PMID:26278805
  • STAG2 and NIPBL (cohesin complex genes) mutated/altered in ~16% of LGG/GBM; nominated as a therapeutic vulnerability for PARP inhibitors and DNA-damage agents PMID:26824661
  • Chromatin regulator in AML chromatin-spliceosome subgroup; co-occurs with splicing factors SF3B1, SRSF2, U2AF1, ZRSR2 and chromatin regulators BCOR, EZH2, PHF6 in the same adverse-risk genomic cluster PMID:27276561
  • Truncating mutations in 23% of non-muscle-invasive bladder cancer (NMIBC; n=105); enriched in low-grade Ta tumors (p=0.046), supporting association with lower-grade/stage disease PMID:28583311
  • Recurrently altered candidate driver across medulloblastoma subgroups in the 491-sample ICGC cohort PMID:28726821
  • Recurrent SMG in MIBC; one of the MutCN cluster definers alongside FGFR3 and KDM6A PMID:28988769

Cancer types (linked)

  • MDS: STAG2 mutations are recurrent drivers; presence of separated megakaryocyte nuclei on biopsy is a potential morphologic indicator of STAG2 mutation status PMID:21909114

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • No direct therapeutic implications established in this study; morphologic surrogates for STAG2 mutations may inform MDS subtyping and patient stratification PMID:21909114

Open questions

  • The precise mechanistic link between STAG2 (cohesin complex) loss and megakaryocyte nuclear separation remains unclear.
  • Whether separated megakaryocyte nuclei are specific enough to replace sequencing-based STAG2 detection in clinical practice has not been prospectively validated.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:23634996

This page was processed by crosslinker on 2026-05-14. - PMID:24121792

This page was processed by crosslinker on 2026-05-14. - PMID:24476821

This page was processed by crosslinker on 2026-05-14. - PMID:25092538

This page was processed by crosslinker on 2026-05-14. - PMID:25223734

This page was processed by crosslinker on 2026-05-14. - PMID:26278805

This page was processed by crosslinker on 2026-05-14. - PMID:26824661

This page was processed by entity-page-writer on 2026-05-15. - PMID:27276561

This page was processed by entity-page-writer on 2026-05-15. - PMID:28583311

This page was processed by wiki-cli on 2026-05-15. - PMID:28726821

This page was processed by wiki-cli on 2026-05-15. - PMID:28988769

This page was processed by wiki-cli on 2026-05-15.