KIT – Gastrointestinal Stromal Tumor

KIT is the predominant oncogenic driver in gastrointestinal stromal tumors (GISTs), with activating mutations detected in over 80% of sporadic cases (PMID:31966753). Germline KIT variants underlie familial GIST syndromes with an autosomal dominant inheritance pattern, manifesting as multifocal tumors and interstitial cell hyperplasia. Functional concordance across models—from Ba/F3 cell proliferation assays to murine xenografts—demonstrates ligand‐independent kinase activation for juxtamembrane and kinase domain mutations, confirming KIT’s pathogenic role.

Genetic studies have identified over 49 kindreds segregating germline KIT mutations (PMID:37311038). Recurrent missense and in-frame deletion variants in exon 11 (juxtamembrane) and exon 17 (kinase I) show complete co-segregation with disease in affected relatives. One widely reported variant is c.1669T>C (p.Trp557Arg), present in multiple generations and associated with cutaneous hyperpigmentation and multifocal GIST (PMID:28710566). Somatic KIT mutations are largely mutually exclusive with PDGFRA and BRAF mutations in GIST.

Functional assays reveal that KIT mutants—including p.Asp579del and p.Lys642Glu—undergo constitutive autophosphorylation, drive factor-independent growth in Ba/F3 cells, and induce tumor formation in nude mice (PMID:11073817; PMID:8962111). Transgenic murine models with W-allele KIT alterations recapitulate interstitial cell hyperplasia and pigment cell defects, underscoring the receptor’s role in Cajal cell and melanoblast development.

No studies have refuted KIT’s central role in GIST pathogenesis. KIT mutation status informs diagnostic classification, prognostic risk stratification, and targeted therapy selection—most notably imatinib and next-generation tyrosine kinase inhibitors. Routine testing for KIT exon 9, 11, 13, and 17 mutations is recommended for all GIST patients.

Key Take-home: Definitive genetic and functional evidence establishes KIT mutations as the primary driver of GIST, supporting mutation testing for diagnosis, familial screening, and precision therapy.

References

• The American journal of pathology • 2000 • Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. PMID:11073817
• International journal of clinical and experimental pathology • 2017 • Two new KIT exon 13 mutations in one gastric gastrointestinal stromal tumor (GIST). PMID:31966753
• Familial cancer • 2018 • Remarkable effects of imatinib in a family with young onset gastrointestinal stromal tumors and cutaneous hyperpigmentation associated with a germline KIT-Trp557Arg mutation: case report and literature overview. PMID:28710566
• The Oncologist • 2023 • Diagnosis, Treatment, and Prognosis of Patients with Primary Familial Gastrointestinal Stromal Tumor: A Case Report and Literature Review. PMID:37311038
• Proceedings of the National Academy of Sciences of the United States of America • 1996 • Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1. PMID:8962111

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