Gastrointestinal Stromal Tumors (GIST)

Synonyms: -

Material:

FFPE tissue sections

TAT:

varies depending on the analysis

Method:

NGS

Overview

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. They show differentiation towards the interstitial cells of Cajal or related precursor cells and usually express KIT (CD117), DOG1, or both. Histologically, GIST may have spindle-cell, epithelioid or mixed morphology. The stomach is the most frequent primary site, followed by the small intestine; GIST of the duodenum, rectum, colon, appendix and oesophagus are less common.

Clinical background and relevance

Molecular genetic analysis of GIST tumour tissue has diagnostic and, above all, predictive therapeutic relevance. Most GIST harbour mutually exclusive activating variants in KIT or PDGFRA. The affected gene and exon can determine sensitivity or resistance to specific tyrosine kinase inhibitors (TKIs) and may influence drug selection or dose. Genotyping is therefore recommended before neoadjuvant therapy and whenever systemic treatment is planned. In the adjuvant setting, targeted therapy should be considered only for tumours with a molecular genotype associated with sensitivity to the intended treatment.

Molecular findings can also support the diagnosis in morphologically or immunohistochemically ambiguous cases. However, the absence of a KIT or PDGFRA variant does not exclude GIST, and molecular results must be interpreted together with morphology and immunohistochemistry. SDHB immunohistochemistry is important in the evaluation of KIT/PDGFRA wild-type GIST because loss of SDHB expression identifies SDH-deficient GIST, including tumours caused by an SDH-subunit gene alteration or by epigenetic inactivation. In KIT/PDGFRA wild-type, SDH-competent tumours, broader DNA- and RNA-based testing may identify alternative drivers involving NF1, BRAF, NTRK or FGFR genes.

Identification of an SDH-deficient or multifocal GIST, or clinical features suggestive of a GIST-associated syndrome, may indicate hereditary predisposition. Genetic counselling and assessment for germline testing should therefore be considered, particularly in patients with SDH-deficient GIST, multifocal disease, a suggestive personal or family history, or features of neurofibromatosis type 1 or familial GIST.

GIST subgroups and their clinical relevance

Approximately 80% of GIST harbour a pathogenic variant in KIT and further 5% to 10% in PDGFRA. Among the approximately 10% to 15% lacking alterations in either gene, most are SDH-deficient, while alterations involving NF1, BRAF, NTRK or FGFR represent rarer alternative drivers.

Table 1: GIST subgroups and their clinical relevance

Molecular subgroup	Principal finding	Main clinical relevance
KIT-mutant GIST	Most frequently exon 11; less commonly exon 9 and rarely other exons	Predicts sensitivity to specific TKIs and may influence treatment selection and dose in advanced (exon 9-mutant) disease
PDGFRA-mutant GIST	Frequently exon 18	Identification of TKI-insensitive exon 18 variants, particularly p.Asp842Val, is essential for genotype-directed treatment selection
SDH-deficient GIST	Loss of SDHB expression; may result from an SDHx alteration or epigenetic inactivation	Distinct biological subgroup, usually imatinib-insensitive; may indicate hereditary predisposition
NF1-associated GIST	Inactivation of NF1, often in small-bowel and potentially multifocal GIST	Usually lacks a canonical KIT/PDGFRA driver; may indicate neurofibromatosis type 1
BRAF-mutant GIST	Most often p.Val600Glu	Rare alternative driver with potential matched treatment options
NTRK-fusion-positive tumour	Oncogenic fusion involving NTRK1, NTRK2 or NTRK3	Rare and potentially actionable; the fusion and classification as GIST require integrated pathological and molecular confirmation
FGFR-altered GIST	Rare fusion or other activating alteration involving an FGFR family gene	Potential therapeutic relevance is case-dependent; evidence in GIST remains limited

GIST genotyping is essential when systemic therapy is contemplated because the molecular driver can predict drug sensitivity or resistance. It may also support diagnostically difficult cases and identify biologically distinct or potentially hereditary subgroups. However, molecular findings complement rather than replace clinicopathological risk stratification based primarily on tumour size, mitotic rate, anatomical site and tumour rupture.

Available tests

The sequencing analysis and the fusion gene analysis can be ordered individually or together as one combined targeted analysis. Microsatellite instability analysis may be ordered separately as an additional tumour-agnostic biomarker test when clinically indicated; it is not part of routine GIST-specific molecular classification.

Single-method analysis	Panel	Gene scope	Purpose
Sequencing analysis	Panel00697	BRAF, KIT, NF1, PDGFRA, SDHA	Detection of a sequence variant with potential diagnostic, predictive or therapeutic relevance in tumour tissue
Fusion analysis	Panel00695	FGFR1, FGFR2, FGFR3, NTRK1, NTRK2, NTRK3	Identification of gene fusions in tumour tissue
Microsatellite instability (MSI) analysis	Panel00696	Microsatellite marker analysis	Determination of tumour MSI status

Combined analysis	Panel	Gene scope
Combined targeted analysis	Panel00614	BRAF, KIT, NF1, PDGFRA, SDHA, FGFR1, FGFR2, FGFR3, NTRK1, NTRK2, NTRK3

A negative result does not exclude an SDH-deficient GIST or another molecular driver not covered by the panel. Results should be interpreted together with morphology and immunohistochemistry, including SDHB expression, and supplementary testing may be required. Additional molecular genetic analyses on tumour tissue are also available (see Panel 00617 – ).

Therapy

References

WHO Classification of Tumours Editorial Board. Digestive system tumours. 6th ed., vol. 1. Lyon: International Agency for Research on Cancer; 2026.
European Society for Medical Oncology. ESMO Clinical Practice Guideline: Gastrointestinal Stromal Tumours. Base guideline: Casali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R, et al. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(1):20-33. PMID: .
Serrano C, Martín-Broto J, Asencio-Pascual JM, et al. 2023 GEIS Guidelines for gastrointestinal stromal tumors. Ther Adv Med Oncol. 2023;15:17588359231192388. doi:10.1177/17588359231192388.PMID: ; PMCID: PMC10467260.
Kim Y, Lee SH. Pathologic diagnosis and molecular features of gastrointestinal stromal tumors: a mini-review. Front Oncol. 2024;14:1487467. PMID: . PMCID: PMC11611718.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Gastrointestinal Stromal Tumors, version 1.2026. Most recent partial publication: von Mehren M, Kane JM, Riedel RF, Sicklick JK, Pollack SM, Agulnik M, et al. NCCN Guidelines Insights: Gastrointestinal Stromal Tumors, version 2.2022. J Natl Compr Canc Netw. 2022;20(11):1204-1214. PMID: .
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349. doi: 10.1200/JCO.2003.04.190. PMID: .
Gastrointestinal Stromal Tumor Meta-Analysis Group. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010;28:1247-1253. doi: 10.1200/JCO.2009.24.2099. Epub 2010 Feb 1. PMID: ; PMCID: PMC2834472.
Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour: the NAVIGATOR trial. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020 Jul;21(7):935-946. doi: 10.1016/S1470-2045(20)30269-2. Erratum in: Lancet Oncol. 2020 Sep;21(9):e418. doi: 10.1016/S1470-2045(20)30489-7. PMID: .
Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAF V600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med. 2023;29:1103-1112. doi: 10.1038/s41591-023-02321-8. Epub 2023 Apr 14. PMID: ; PMCID: PMC10202803.
Mathias-Machado MC, de Jesus VHF, Oliveira LJC, et al. Current molecular profile of gastrointestinal stromal tumors and systemic therapeutic implications. Cancers. 2022;14:5330. doi:10.3390/cancers14215330. doi: 10.3390/cancers14215330. PMID: ; PMCID: PMC9656487.
Song IH, Ahn S, Kim HD, Jo JH, Shin J, Ryu MH, et al. Gastrointestinal stromal tumor: history, molecular subtypes, and risk stratification. J Gastric Cancer. 2026;26(2):202-218. PMID: . PMCID: PMC13053826.
Park J, Sul HJ, Kim JG. Rare occurrence of microsatellite instability in gastrointestinal stromal tumors. Medicina (Kaunas). 2021;57(2):174. doi:10.3390/medicina57020174. PMID: ; PMCID: PMC7931009.

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Our editorial team consists of medical specialists and scientists in the field of human genetics. All content is created and reviewed in accordance with current scientific standards.

Last Update : 24.09.2026

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