Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours

Abstract

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet‐derived growth factor‐alpha (PDGFRA) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13–17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.

Approval Summary: Imatinib Mesylate in the Adjuvant Treatment of Malignant Gastrointestinal Stromal Tumors

“…The rate of response in patients with KIT exon 11 mutated GISTs is significantly higher than that in patients with KIT exon 9 mutated or wild-type genotype [9]. In addition, patients with PDGFRA exon 18 mutation D842V are resistant to imatinib therapy, whereas those with mutation D842Y are sensitive [10,11]. These data, if supported by future studies, may better define the resected GIST population who should receive adjuvant imatinib therapy.…”

Prognostic Factors for Survival post Surgery for Patients with Gastrointestinal Stromal Tumors

“…They arise from of the precursor cells of interstitial cell of Cajal and express KIT tyrosine kinase [3]. Different mutation types have been described in GISTs such as c-KIT (the most frequent) and PDGFRA genes [1,4,5,14,15,16]. The physiopathology and treatment of GISTs is different from epithelial neoplasms in the alimentary tract.…”

“…Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms located in the alimentary tract (from the oesophagus to the anus), although they comprise only 0.1–0.3% of all gastrointestinal neoplasms [1,2,3,4,5,6]. The stomach is the most frequent location of GIST (60–70%), with other locations being: small intestine (25–35%), rectum (5%), colon (1%), oesophagus (1–3%).…”

Platelet-Derived Growth Factor Receptor-Alpha D842v Mutation in a Spindle Cell Type Gastrointestinal Stromal Tumor: A Case Report

“…[5][6][7] The most common KIT mutations are detected in exon 11 (66-71%), exon 9 (10-13%), exon 13,14,17 (1% each). PDGFRA mutations (8%) are described in exon 18 (5-6%), exon 12 (1%) and exon 14 (1%).…”