Tyrosine-kinase mutations in c-KIT and PDGFR-alpha genes of imatinib naïve adult patients with gastrointestinal stromal tumours (GISTs) of the stomach and small intestine: relation to tumour-biological risk-profile and long-term outcome

• Published in: Clinical & translational oncology 2012-08, Vol.14 (8), p.619-629
• Main Authors: Søreide, Kjetil, Sandvik, Oddvar M., Søreide, Jon Arne, Gudlaugsson, Einar, Mangseth, Kjersti, Haugland, Hans Kristian
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Benzamides - therapeutic use; Disease-Free Survival; DNA Mutational Analysis; Exons; Female; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - pathology; Gastrointestinal Stromal Tumors - surgery; Humans; Imatinib Mesylate; Intestinal Neoplasms - genetics; Intestinal Neoplasms - pathology; Intestinal Neoplasms - surgery; Intestine, Small - drug effects; Intestine, Small - pathology; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation; Oncology; Piperazines - therapeutic use; Proto-Oncogene Proteins c-kit - genetics; Pyrimidines - therapeutic use; Receptor, Platelet-Derived Growth Factor alpha - genetics; Research Article; Risk Assessment; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Stomach Neoplasms - surgery
• ISSN: 1699-048X; 1699-3055
• DOI: 10.1007/s12094-012-0851-x

Background The identification of activating mutations in either c-KIT cell surface growth factor receptor or platelet-derived growth factor receptor alpha (PDGFRA) has lead the way for the development of novel agents that selectively inhibit key molecular events in gastrointestinal stromal tumour (GIST) pathogenesis. The aim of this study was to investigate the role of c-KIT and PDGFRA gene mutations in primary resectable, imatinib naïve GISTs located in the stomach and small intestine. Methods All adult patients with GIST located in either stomach or small intestine who underwent surgical resection without prior imatinib (Glivec) treatment were included. DNA extraction and mutational analysis were performed. Mutational analyses were performed for c-KIT (exons 9, 11, 13, and 17) and the PDGFRA genes (exons 12, 14 and 18). Clinical and pathological parameters were analyzed in relation to the mutations in c-KIT and PDGFRA. Results A total of 38 patients who underwent surgery for GIST located in either the stomach ( n  = 24) or in the small intestines ( n  = 14) were included. Mutations were found in 31 of 38 (81.6 %) patients, with 24 (63.2 %) located in c-KIT and 7 (18.4 %) in the PDGRFA exons, respectively. Seven patients (18.4 %) were wildtype ( WT ). The most common mutation was in c-KIT exon 11. Incidentally found GISTs were significantly smaller (size >5 cm in 15 % for incidental vs. 71 % for symptomatic; OR of 13.4, 95 % CI 2.3–76.5; P  = 0.001) and had lower mitotic rate (0 % for incidental vs. 44 % of the symptomatic; OR 0.52, 95 % CI 0.36–0.75; P  = 0.005). Accordingly, the Fletcher grade was significantly better for incidental cases, with most having very low or low risk (85 %) in contrast to 19 of 25 (76 %) symptomatic cases showing moderate to high-risk features (OR 17.4, 95 % CI 2.98–101.7; P