Novel Genomic Risk Stratification Model for Primary Gastrointestinal Stromal Tumors (GIST) in the Adjuvant Therapy Era

Authors

Josephine K. Dermawan

Ciara Kelly

Zhidong Gao

Shaleigh Smith

Bhumika Jadeja

Samuel Singer

William D. Tap

Ping Chi

Cristina R. Antonescu

Doi

10.1158/1078-0432.CCR-23-1184

PMID: 37477937 · DOI: 10.1158/1078-0432.CCR-23-1184 · Journal: Clinical Cancer Research (2023)

TL;DR

Dermawan et al. profiled 501 GIST patients (592 samples) from MSKCC with MSK-IMPACT targeted sequencing and built an elastic-net penalized Cox machine learning model to create a 3-tier genomic risk stratification for recurrence-free survival in 152 primary localized gastric and 80 small bowel GISTs. The genomic model, incorporating arm-level CNAs (chr1p, chr14q, chr5q, chr1q) and gene alterations (SDHB, KIT exon 11, MAX/MGA/MYC, CDKN2A, RB1), both upgrades and downgrades patients compared to conventional Miettinen/NIH-Fletcher/Joensuu schemes, suggesting the traditional approaches may under- or over-treat subsets of patients in the imatinib/TKI adjuvant era PMID:37477937.

Cohort & data

  • 501 patients (592 samples) with GIST diagnosed at MSKCC between 1991 and 2021: 275 gastric (307 samples), 194 small bowel (244 samples), 32 rectal (41 samples; excluded from analyses).
  • Primary localized gastric (n=152) and small bowel (n=80) GISTs analyzed for risk stratification; 41% of gastric and 53% of small bowel received adjuvant imatinib.
  • Cancer type: GIST.
  • Dataset/cohort: gist_msk_2023.
  • Assay: MSK-IMPACT targeted DNA NGS (341–505 genes), matched tumor-normal.

Key findings

  • A 3-tier genomic risk stratification model was developed separately for gastric and small bowel GISTs using an elastic-net penalized Cox proportional hazards model.
  • Gastric GISTs: high risk if chr1p deletion or SDHB loss; intermediate risk if chr14q deletion or absence of KIT exon 11 mutation.
  • Small bowel GISTs: high risk if MAX/MGA/MYC, CDKN2A, or RB1 alterations; intermediate risk if chr1p deletion or chr5q amplification.
  • Compared with conventional Miettinen/NIH-Fletcher/Joensuu stratification, the genomic model both upgraded and downgraded patients, indicating conventional models may underestimate risk in some and overtreat others.
  • Longitudinal sequencing detected most KIT-independent genomic alterations already at baseline.
  • In a subanalysis of 26 SDH-deficient GISTs, presence of TP53 mutations or chr1q amplification was associated with worse recurrence-free and disease-free survival.

Genes & alterations

  • KIT — exon 11 mutation status incorporated into gastric risk model; absence flagged as intermediate risk.
  • PDGFRA — co-primary GIST driver; KIT/PDGFRA wild-type cases with SDHB IHC loss classified as SDH-deficient.
  • SDHB — loss of protein expression defines high-risk gastric GIST in the genomic model.
  • SDHA — assessed for germline/somatic mutation in SDH-deficient subset.
  • TP53 — mutations portend worse RFS/DSS in SDH-deficient GIST subset.
  • CDKN2A — alterations define high risk in small bowel GIST.
  • RB1 — alterations define high risk in small bowel GIST.
  • MAX, MGA, MYC — any alteration in this set defines high risk in small bowel GIST.

Clinical implications

  • Genomic risk stratification may refine selection of patients for adjuvant imatinib therapy by identifying high-risk patients missed by conventional models and by sparing some low-risk patients from overtreatment.
  • SDH-deficient GISTs harboring TP53 mutation or chr1q amplification represent a prognostically worse subgroup warranting closer surveillance.
  • Authors emphasize the model complements rather than replaces clinicopathologic stratification and requires independent external validation.

Limitations & open questions

  • Single-institution retrospective cohort from MSKCC; requires external validation as explicitly noted by the authors.
  • DSS could not be examined in the primary localized cohort due to insufficient events.
  • Rectal GISTs were excluded from modeling.
  • SDH-deficient subanalysis is small (n=26).
  • Generalizability to non–MSK-IMPACT panels and to patients not receiving adjuvant TKI is uncertain.

Citations from this paper used in the wiki

  • “A 3-tier genomic risk stratification model for recurrence-free survival (RFS) in 152 primary localized gastric and 80 small bowel GISTs was proposed.” (Abstract)
  • “Gastric GISTs were classified as high risk if chr1p deletion or SDHB loss was present, and intermediate risk if chr14q deletion was present or KIT exon 11 mutation was absent.” (Abstract)
  • “Small bowel GISTs were classified as high risk if MAX/MGA/MYC, CDKN2A or RB1 alterations was present, and intermediate risk if chr1p deletion or chr5q amplification was present.” (Abstract)
  • “Subanalysis in 26 SDH-deficient GISTs revealed that presence of TP53 mutations or chr1q amplifications portends worse RFS and disease-free survival.” (Abstract)
  • “Comprehensive mutational and copy number profiling using MSK-IMPACT was performed.” (Abstract)

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