title: No KRAS mutations found in gastrointestinal stromal tumors (GISTs): molecular genetic study of 514 cases.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. A great majority of GISTs is driven by pathological activation of KIT or platelet-derived growth factor receptor-α (PDGFRA), two closely related receptor tyrosine kinases. However, other genetic changes including gain-of-function BRAF mutations and loss of succinate dehydrogenase (SDH) complex activity have been identified in the subsets of KIT-, PDGFRA-wild type tumors. Genetic mutations affecting KIT, PDGFRA, BRAF and SDH complex functions are believed to be mutually exclusive events. Recently, KRAS codon 12 and 13 mutations were reported in a small subset of KIT or PDGFRA mutant GISTs. Moreover, in in vitro experiments, KIT mutants with concurrent KRAS mutation showed resistance to imatinib, a receptor tyrosine kinase inhibitor used in GIST treatment. The aim of this study was to evaluate a large cohort of GISTs to define frequency and clinical significance of KRAS mutations in this type of cancer. A well-characterized cohort of 514 GISTs was screened for KRAS mutations using Sanger sequencing (n=450) and pyrosequencing (n=64). In all, 350 gastric, 100 intestinal and 64 primary disseminated GISTs were analyzed. No KRAS mutations were found. In GIST, KRAS mutations are extremely rare if they exist (<0.2%). Thus, mutational activation of KRAS does not seem to play any significant role in the development and progression of this type of cancer.
authors.affiliation: Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lasota
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.forename: Tiffany
authors.initials: T
authors.lastname: Coates
authors.forename: RaShonda
authors.initials: R
authors.lastname: Dennis
authors.forename: Moses O
authors.initials: MO
authors.lastname: Evbuomwan
authors.forename: Zeng-Feng
authors.initials: ZF
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
mesh_terms: D004252:DNA Mutational Analysis; D018450:Disease Progression; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins