Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.

Gastrointestinal stromal tumors: what do we know now?

“…[51][52][53][54][55][56] Most arise in the small intestine and they do not readily metastasize. 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).…”

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

“…Biallelic inactivation of NF1, with one allele constitutionally inactivated and the other somatically mutated, is required for benign and malignant tumor formation (17). Accordingly, evidence of NF1 loss of heterozygosity (LOH) has been observed in PCC (13), GIST (18,19), and MPNST (20)(21)(22). However, the molecular mechanisms of NF1 tumorigenesis remain unclear.…”

“…2). However, 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed no accumulation on adrenal tumors, and no other abnormal uptake was observed. We diagnosed PCCs in bilateral adrenal glands and GIST in the duodenum associated with NF1.…”

Gastrointestinal stromal tumours in patients with type 1 neurofibromatosis

“…The product of the gene, neurofibromin is a GTP-ase protein which regulates cell proliferation and cell differentiation through the ras oncogene. An occurring mutation leads to loss of the gene's function, activation of ras signal transduction cascade and development of benign and malignant tumours [11][12][13][14][15].…”