Gastrointestinal Stromal Tumor (GIST)

Overview

Mesenchymal GI neoplasm typically driven by KIT or PDGFRA mutation.

sarc_mskcc: 22 GIST patients (10.6% of 207 high-grade STS; epithelioid, spindle, and mixed histologies), profiled by targeted resequencing (722 genes) and 250K SNP-array SCNA. PMID:20601955
gist_msk_2023 — 501 patients (592 samples) at MSKCC 1991–2021; 275 gastric, 194 small bowel, 32 rectal; 152 primary localized gastric and 80 small bowel GISTs analyzed for genomic risk stratification PMID:37477937.

KIT — frequent activating mutations in GIST; also found unexpectedly in one myxoid/round-cell liposarcoma sample. PMID:20601955
PDGFRA — recurrent driver in GIST alongside KIT; motivates imatinib therapy as the paradigm for genotype-directed sarcoma treatment. PMID:20601955
Relatively normal karyotype: GIST clusters with SYNS and MRLS as low-complexity subtypes by copy-number analysis. PMID:20601955
KIT exon 11 mutation status, chr1p deletion, chr14q deletion, and SDHB loss incorporated into a gastric GIST risk model PMID:37477937.
Small bowel GIST high-risk features: MAX/MGA/MYC, CDKN2A, or RB1 alterations; intermediate-risk: chr1p deletion or chr5q amplification PMID:37477937.
In 26 SDH-deficient GISTs, TP53 mutations or chr1q amplification portended worse recurrence-free and disease-free survival PMID:37477937.
Longitudinal sequencing detected most KIT-independent genomic alterations already at baseline PMID:37477937.
GIST patients with KIT exon 9 mutations showed distinct response patterns to imatinib compared to those with exon 11 mutations in a large retrospective cohort PMID:36593350
In the MSK-IMPACT pan-cancer cohort, GIST had the highest proportion of OncoKB-actionable alterations at 76% of patients — the highest of all 62 principal tumor types in msk_impact_2017. PMID:28481359

Gastric, small bowel, rectal, and SDH-deficient (KIT/PDGFRA wild-type) GISTs analyzed separately PMID:37477937.

The KIT/PDGFRA → imatinib paradigm is explicitly invoked as the model for subtype-specific molecularly targeted sarcoma therapy. PMID:20601955
A 3-tier genomic risk stratification model derived by elastic-net penalized Cox regression may refine selection for adjuvant imatinib, both upgrading and downgrading patients compared with conventional Miettinen/NIH-Fletcher/Joensuu schemes PMID:37477937.

PMID:37477937
PMID:20601955 — Barretina et al. Nature 2010. Integrative genomic analysis of 207 high-grade soft tissue sarcomas across seven subtypes (MSKCC Sarcoma Genome Project).

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