Unraveling the spectrum of KIT mutations in gastrointestinal stromal tumors: An Indian Tertiary Cancer Center Experience

Abstract

Background:Primary mutations in the KIT gene are the driving force for gastrointestinal stromal tumors (GIST) tumorigenesis. Predictive role of KIT mutation status aids oncologists in patient management. There is a paucity of comprehensive data on the frequency of mutations in the KIT gene in GIST affecting Indian patients. The aims of this study were to determine the frequency and spectrum of molecular alterations affecting the KIT gene and assess their association with clinicopathologic features in a cohort of patients of GIST.Materials and Methods:Morphological and immunohistochemically confirmed GIST cases (n = 114) accessioned from August 2014-June 2015 were analyzed for mutations in KIT exons 9, 11, 13, and 17 and subjected to Sanger sequencing onto the ABI 3500 Genetic Analyzer. The sequences were analyzed using sequence analysis software: SeqScape® and Chromas Lite.Results:KIT mutations were seen in 70% of cases and the majority of KIT mutations involved exon 11 (57%), followed by exon 9 (10%), exon 13 (3%), and exon 17 (1%). Most common exon 11 mutations were in-frame deletions (61.4%) followed by substitution mutations (19.3%). Exon 9 mutations showed identical duplication of Ala-Tyr at codons 502–503. Simultaneous mutations affecting exon 11 and 13 were discovered. Novel variations, namely, p.Q556E (c.1666C>G), p.Q556dup (c.1666_1668dupCAG), p.K558_V559delinsS (c.1672_1677delAAGGTTinsAGT), p.Y503_F504insTY (c.1509_1510insACCTAT), and p.K642R (c.1925A>G) involving exons 11, 9, and 13, respectively, were observed.Interpretation and Conclusions:First study with complete analysis of all 4 exons of KIT (exons 9, 11, 13, and 17) in Indian GIST patients. Along with well-described KIT mutations, several rare double mutations as well as novel alterations were reported in this series.

Nationwide evaluation of mutation-tailored treatment of gastrointestinal stromal tumors in daily clinical practice

“…An overview of the molecular landscape of GIST cases showed KIT mutations in 74.8% of the cases, PDGFRA mutations in 14.8% of the cases, and 10.4% of the cases were KIT/PDGFRA wildtype, which was in line with other studies [15,[39][40][41][42][43][44][45]. Although numbers were limited, patients with metastatic disease and PDGFRA mutations had a poor OS compared to the remaining metastatic disease patients.…”

Analysis of C-Kit Exon 9, Exon 11 and BRAFV600E Mutations Using Sangers Sequencing in Gastrointestinal Stromal Tumours

“…The most common mutation was tryptophan557_lysine558 del (c.1669_1674delTGGAAG) in 13 cases. The substitution mutations were Val559Asp, Val560Asp, Val559Ala, Val560Gly, Thr574Ile and Leu576Pro; among these nine were homozygous and two were heterozygous [21]. This was not in concordance with our study as we reported different set of missense mutations.…”

“…Nine tumours were present in the small intestine and one in the retroperitoneum. All the tumours had a spindle cell morphology [21]. Lux et al and Lasota et al in their studies found heterozygous exon 9 mutations in GISTs.…”

Identification of CFTR as a novel key gene in chromophobe renal cell carcinoma through bioinformatics analysis

“…KIT , a receptor tyrosine kinase, can activate several signaling pathways, including the PI3K-Akt signaling pathway (21). Mutations of KIT are associated with gastrointestinal stromal tumors, lung cancer and other tumor types (22). ALDOA , a member of the class I fructose- bisphosphate aldolase protein family, may contribute to tumorigenesis and the progression of pancreatic and lung cancer (23).…”