Gastrointestinal stromal tumours in patients with type 1 neurofibromatosis

Abstract

Abbreviations AKT = protein kinase B; GIST = gastrointestinal stromal tumour; PDGFRA = platelet-derived growth factor receptor alpha; ICC = intestinal cell of Cajal; JAK = Janus-activated kinase; MAPK = mitogen-activated protein kinase; mTOR = mammalian target of rapamycin; NF1 = neurofibromatosis 1; NF/GIST = neurofibromatosis-associated GIST; PI3K = phosphatidylinositol-3-kinase; STAT = signal transducer and activator of transcription Type 1 neurofibromatosis, also known as von Recklinghausen's disease, is one of the most common diseases with autosomal dominant inheritance. The gene of neurofibromatosis, an NF1 tumour suppressor gene, is located on Chromosome 17. Due to the loss of tumour suppressor function, mutation of the gene leads to the development of benign and malignant tumours. Gastrointestinal manifestations, most often gastrointestinal stromal tumour (GIST), are found in 25% of cases. The close association of the two diseases is well known in the literature, with more than 160 cases reported up to now. GIST develops in 7% of patients with neurofibromatosis, and the occurrence of NF1 among patients with GIST is 150 to 180 times more frequent than in the general population. GIST associated with neurofibromatosis is a separate entity, and unlike sporadic GIST it is usually multiple and it almost always develops in the small intestine. It manifests itself usually at a younger age, with a slight female dominance. Its histological characteristics include spindle cell type, the presence of skeinoid bodies, and frequent S100 positivity. Its low mitotic activity usually suggests a more favourable prognosis. C-KIT and PDGFRA mutations characteristic of sporadic GIST occur very rarely, in accordance with the hypothesis that the pathogenesis of neurofibromatosis-associated GIST is not c-KIT dependent. Presumably the pathomechanism of GIST associated with neurofibromatosis is different from that of the sporadic form, and the occurrence of GIST tumour is a part of the clinical spectrum of neurofibromatosis. In the few known cases mutations of c-KIT and PDGFRA probably develop at a late step of tumour genesis. Imatinib that has revolutionized GIST therapy is not efficient in this group of patients; however there are no sufficient data available yet.

An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST)

“…In particular, in a set of 13 GIST tumour samples (9 mutant vs 4 WT GIST) 56 microRNAs differentially expressed at a 0.05 cut-off p value between WT and mutant samples were found46 By correlation with gene expression profiling data, hsa-let-7b and hsa-let-7c microRNAs were the most significantly differentially expressed microRNAs; they were less expressed in WT samples and were able to target the IGF1R receptor 49…”

“…NF1, also known as von Recklinghausen disease, is an inherited, autosomal dominant disease phenotypically characterised by multiple café au lait spots, Lisch nodules, freckling and development of neurofibromas and, in some cases, their malignant derivatives, including GIST 45 46. GIST in NF1 patients arise predominantly from the small intestine, are possibly multicentric and lack KIT and PDGFRA mutations 47.…”

Succinate Dehydrogenase Subunit B (SDHB) Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists): Implications for the SDHB Expression Based Classification of Gists

“…Also, gastrointestinal stromal tumors (GISTs) arise in NF1 patients 150 times more frequently than in the general population 2. With an estimated birth incidence of 1:3000 in Western countries, NF1 is the most commonly inherited disease 1.…”

“…Neurofibromatosis-1 (NF1), also known as von Recklinghausen disease, is an inherited, autosomal dominant disease phenotypically characterized by multiple café au lait spots, Lisch nodules, freckling, and development of neurofibromas, and in some cases, their malignant derivatives 1 . Also, gastrointestinal stromal tumors (GISTs) arise in NF1 patients 150 times more frequently than in the general population 2 . With an estimated birth incidence of 1:3000 in Western countries, NF1 is the most commonly inherited disease 1 .…”

Recent advances in managing gastrointestinal stromal tumor

“…The subgroup of the remaining KIT/PDGFRA wild-type, but not SDH-deficient, GISTs have been further characterized: about 15% possess an activating mutation in BRAF or, more infrequently, a RAS gene 64 . Furthermore, wild-type GISTs may appear in the setting of syndromic neurofibromatosis type I (NF1) disease, in which there is a loss of function of the NF1 protein 65 . Together, GISTs with mutations in BRAF/RAS or NF1 are known as RAS pathway (RAS-P) mutant GISTs.…”