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.

Novel oncogene and tumor suppressor mutations in KIT and PDGFRA wild type gastrointestinal stromal tumors revealed by next generation sequencing

“…The prevalence of KRAS mutation in GISTs ranges from <0.2% of all GISTs (Lasota et al, 2013) to, in our series of eight wild type GISTs, 11%. In 2012, Miranda et al first described the occurrence of KRAS mutations in GISTs in three patients, two of which harbored KIT mutations and one of which harbored a PDGFRA mutation.…”

Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases

“…9,18 Based on previous studies, the frequency of RAS mutations in imatinib-naive GISTs remains very low. 19 More recently, a KRAS G12V mutation at 29% allele frequency has been reported in an SDH-deficient highly malignant gastric GIST. 20 No PIK3CA, HRAS, and KRAS mutations were identified in 16 SDH-deficient GISTs analyzed in this study.…”

On the prevalence of KRAS mutations in GISTs

“…A recent paper by Lasota et al reported about the absence of KRAS mutations in a large cohort of GISTs (n =514) [3] which, to the best of our knowledge, constitutes by itself about 60 % of cases so far studied for this molecular alteration [4][5][6][7]. Thus, considering the cumulative evidence produced so far, the actual possible prevalence of KRAS mutations in GISTs seems much lower than the one we hypothesized, possibly approaching 0.3 %.…”