Analysis of mutation of the c-Kit gene and PDGFRA in gastrointestinal stromal tumors

Abstract

The aim of the present study was to investigate mutation status of the and in patients with a gastrointestinal stromal tumor (GIST). In total, 93 patients with a GIST were included in the study, in which polymerase chain reaction amplification and gene sequencing were used to detect the sequences of exons 9, 11, 13 and 17 in and exons 12 and 18 in. mutations were detected in 64 cases (68.82%), of which exon 11 mutations were detected in 56 cases (60.22%), exon 13 mutations were detected in three cases (3.23%) and one case (1.08%) was shown to have a mutation in exon 17. The most common mutation in exon 11 was a deletion, which accounted for 55.36% (31/56) of the cases, followed by a point mutation observed in 26.79% (15/56) of the cases, while an insertion (tandem repeats) was identified in 14.29% (8/56) of the cases, and 3.57% (2/56) of the exon 11 mutations were deletions associated with a point mutation. The majority of the mutations were heterozygous, with only a few homozygous mutations. Mutational analysis revealed the mutations to be more concentrated in the classic hot zone at the 5'-end, followed by the tandem repeat frame at the 3'-end. In four cases, a mutation was detected in exon 18 of, of which one was associated with a mutation in . The remaining three cases (10.34%, 3/29) were not associated with mutations in and accounted for 37.5% (3/8) of the CD117-negative GIST cases. Therefore, the majority of the GIST cases were characterized by mutations in or, which were directly associated with the disease. Pairs of different mutations in the same exon of , or mutations coupled with pairs of mutations in , were detected in a small number of patients. Imatinib is a small molecule tyrosine kinase inhibitor and is the first line targeted treatment for GIST, resulting in markedly improved survival rates. Thus, gene mutation genotyping may provide inspiration and guidance for imatinib-based targeted cancer therapy.

Preoperative adjuvant therapy for locally advanced and recurrent/metastatic gastrointestinal stromal tumors: a retrospective study

“…Similar findings have been found by Heinrich et al [27] and Debiec-Rychter et al [28]. Patients with KIT exon 17 mutations can rarely be detected in GISTs, and their response to imatinib is variable; in most cases, they respond well to imatinib therapy [29][30][31]. In addition, approximately 10% of GIST patients have no mutation in either KIT or PDGFRA, and these tumors are called wild-type GISTs and have an approximately 0% to 45% likelihood of a response to imatinib [8,23].…”

Preoperative adjuvant therapy for locally advanced and recurrent/metastatic gastrointestinal stromal tumors: a retrospective study

“…Similar findings have been found by Heinrich MC et al[27] and Debiec-Rychter M et al[28]. Patients with KIT exon 17 mutations can rarely be detected in GISTs, and their response to imatinib is variable; in most cases, they respond well to imatinib therapy[29][30][31]. In addition, approximately 10% of GIST patients have no mutation in either KIT or PDGFRA, and these tumors are called wild-type GISTs and have an approximately 0-45% likelihood of a response to imatinib[8,23].…”

Heredo-Familial and Pediatric GISTs: Spot the Differences

“…This is a molecule with also a tyrosine kinase activity. The pathway that follows the activation of the receptor is basically similar to that of c-KIT [23,25]. The most frequent genetic alterations in c-KIT and PDGFRA including missense mutations as well as insertions and deletions are summarized in Tables 1, 2, respectively.…”

“…Moreover, since PDGFRA and c-KIT genes share a high amino acid sequence homology, the functional consequences of their alterations are similar. Indeed, in both cases the mutations can generate autophosphorylation, which triggers the activation of two main signaling pathways, the RAS-RAF-MEK-ERK and the PI3K-AKT-mTOR cascades, which leads to uncontrolled cell growth [25].…”

“…Indeed, a percentage of GIST cases that show no mutations in c-KIT exhibits alterations in PDGFRA gene (platelet-derived growth factor receptor), with a mutually exclusive relationship. The codifying sequence contains 23 exons and preferred mutational "hot spot" falling in exons 12, 18 and 14 [25]. The gene sequence encodes for a molecule with tyrosine kinase activity with similar function to c-KIT [26,27].…”