Mutations in c‐kit Gene Exons 9 and 13 in Gastrointestinal Stromal Tumors among Japanese

Abstract

Gain-of-function mutation in c-kit proto-oncogene exon 11 has been described in about 20-50% of gastrointestinal stroma tumor (GIST). Recently, additional mutational hot-spots in exon 9 and exon 13 of the c-kit gene have been reported in GISTs without mutations of exon 11, but a subsequent report in a Western population indicated that only a small portion of GISTs (eight of 200 GISTs, 4%) showed mutations in these regions. In this study, we evaluated mutations in exon 9 and exon 13 of the c-kit gene by both polymerase chain reaction-single strand conformation polymorphism analysis and direct sequencing in 48 GISTs in a Japanese population, for which the clinicopathological and immunohistochemical features and mutations in exon 11 had previously been reported. C-kit gene mutation in exon 9, representing insertion of GCC TAT, was identified in only 4 of 48 GISTs (8%), and none of the GISTs had mutations in exon 13. All four GISTs with mutation in exon 9 were high-risk, and the patients died of multiple tumor metastasis. Mutations in exon 9 and exon 13 of the c-kit gene were also rare events in Japanese GISTs and were related to a poor prognosis. These results in Japanese are consistent with those in Western populations, although a preferential occurrence of GISTs with exon 9 mutation in the small intestine, which was suggested in a previous report, was not observed.

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

“…16,54 The presence of two different KIT or PDGFRA mutations affecting the same or different exons has been reported in a few cases. 42,[55][56][57][58] More recently, double KIT exon 11 mutations have been found in as many as 9% (7 of 78) of primary tumors in 1 study. 59 Also, coexistence of missense and silent KIT exon 11 mutations and missense and nonsense KIT exon 11 mutations was reported twice in the primary tumors.…”

“…39 A subsequent study of a relatively large number of GISTs from different locations estimated the frequency of this mutation to be no higher than 2.5%. 40,56 Recent studies on GISTs, based on Asian population, have reported three tumors with unique missense mutations (Leu641Pro, Val643Ala, and Leu647Pro) affecting KIT exon 13 in the vicinity of Lys642. The biological potential of these mutations is uknown.…”

“…71,74 However, gastric GISTs with 1525_1530dupGCCTAT have been also reported in the literature. 56,75,76 Based on Western population studies, 64,66,74,[76][77][78][79][80][81] such tumors represent only 6.6% of all KIT exon 9 mutant GISTs. In contrast, combined studies from Asia 56,75,82-84 indicated almost 32% frequency of gastric GISTs among all KIT exon 9 mutants (Table 1).…”

c‐kit gene mutations in intracranial germinomas

“…1-3) On the other hand, gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT have been reported in tumors arising from these cell lineages, such as mast cell tumors, 4,5) gastrointestinal stromal tumors (GISTs), [6][7][8][9][10][11][12][13] which are thought to originate from ICCs in the gastrointestinal tract, and germ cell tumors (GCTs).…”

“…The ligand for KIT is stem cell factor (SCF). The SCF-KIT system is critical for the normal development and survival of melanocytes, erythrocytes, germ cells, mast cells, and interstitial cells of Cajal (ICCs).1-3) On the other hand, gain-of-function mutations of the c-kit gene and the expression of phosphorylated KIT have been reported in tumors arising from these cell lineages, such as mast cell tumors, 4,5) gastrointestinal stromal tumors (GISTs), [6][7][8][9][10][11][12][13] which are thought to originate from ICCs in the gastrointestinal tract, and germ cell tumors (GCTs).14-18) Four mutational hot spots in different regions of the c-kit gene have been identified: in exons 9, 11, 13, and 17. More recently, an additional activating c-kit gene mutation has been detected at exon 10 encoding the transmembrane domain.…”