Absence of c‐kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients

Abstract

Most sporadic gastrointestinal stromal tumours (GISTs) have somatic c-kit gene mutations that are considered to be causal. Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and NF1 patients have an increased risk of developing GISTs. Since most neoplasms are considered to develop as a result of the combination of several gene mutations, these findings suggest that GISTs from NF1 patients might have somatic c-kit gene mutations and that sporadic GISTs from non-NF1 patients might have somatic NF1 gene mutations. The present study analysed 29 GISTs from seven NF1 patients for c-kit gene mutations and ten sporadic GISTs from ten non-NF1 patients for NF1 mutations. Exons 9, 11, 13, and 17 of the c-kit gene were amplified and directly sequenced after the extraction of genomic DNA from wax-embedded tissues from 26 GISTs from five NF1 patients. The whole coding region of the c-kit cDNA and the whole coding region of the NF1 cDNA were amplified and directly sequenced after RNA extraction and cDNA synthesis in three fresh GIST tissues from two NF1 patients and ten fresh GIST tissues from ten non-NF1 patients. Of the ten sporadic GISTs, eight had heterozygous mutations at exon 11, and one at exon 9, of c-kit. Heterozygous NF1 gene mutations were detected in GISTs from the two NF1 patients from whom fresh tissues were available. None of the 29 GISTs derived from NF1 patients had detectable c-kit gene mutations and none of the ten GISTs derived from non-NF1 patients had detectable NF1 mutations. These results suggest that the pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.

Gastrointestinal stromal tumors: what do we know now?

“…51 The majority of these GISTs are wild type for KIT and PDGFRA, but as expected they do show either somatic mutation or loss of the remaining wild-type NF1 allele, resulting in signaling through the MAP kinase cascade (Figure 3b). 51,54,55,57 …”

A Case of Neurofibromatosis Type 1 Coinciding with Bilateral Pheochromocytomas, Multiple Gastrointestinal Stromal Tumors, and Malignant Peripheral Nerve Sheath Tumor

“…Neurofibromin downregulates Ras through its GAP-related domain; thus, at decreased levels in NF1, signaling is increased through all of these pathways, resulting in cell proliferation and inhibition of apoptosis (2). NF1-associated GISTs were reported to lack c-kit or PDGFRA mutations, which are typically observed in sporadic GIST (14,15,23). Because the mutations of c-kit result in constitutive activation of the Ras/MAPK pathway as well as of the Akt/mTOR pathway, overlapping signaling pathways may be involved in the molecular pathogenesis of NF1-associated GIST and sporadic GIST (24).…”

GISTs múltiplos em neurofibromatose tipo 1: diagnóstico incidental em paciente com abdome agudo

“…O presente relato está em conformidade com outras publicações, que teem demonstrado que a associação de GIST e neurofibromatose tipo 1 não é casual 1,7,10,14,15 . Em particular, a faixa etária acometida pelos GISTs na neurofibromatose tipo 1 é menor do que em casos isolado5.…”

“…No presente relato, a positividade para CD-34 e c-KIT demonstrou perfil compatível com GIST. Entretanto, acredita-se que os GISTs associados à neurofibromatose tipo 1 surjam de uma rota alternativa, já que a positividade para mutações c-KIT e PDGFRA muitas vezes não é encontrada 7,9 , diferente dos GISTs esporádicos que apresentam tais mutações.…”