Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor

Abstract

Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G --> A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5' ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

“…16,43,117 KIT and PDGFRA mutational status in NF1 and pediatric and Carney triad GISTs Several studies evaluated KIT and PDGFRA mutation status in GISTs from neurofibromatosis type 1 (NF1) patients. [118][119][120][121][122][123][124] In general, no mutations in GIST-specific KIT or PDGFRA mutational "hot spots" have been found in multiple tumors from NF1 patients. However, one study identified two KIT (Pro627Leu and Ile653Thr) and two PDGFRA (Pro589Lys and Arg822Ser) missense mutations in two separate lesions from two patients.…”

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

“…Because positive staining for KIT has been required for the diagnosis and nosology of GISTs since 1998, it is possible that these tumors were reported as separate tumors in previous reports (5). To our knowledge, there have been 8 documented cases, including the present case, of concurrent PCC and GIST (6)(7)(8)(9)(10)(11), and only 2 cases of concurrent PCC, GIST, and MPNST (11). PCCs are generally bilateral, and GISTs are generally multiple.…”

Gastrointestinal stromal tumours in patients with type 1 neurofibromatosis

“…At the same localisation carcinoma was observed in one case [40]. The cumulative occurrence of phaeochromocytomas in von Recklinghausen's disease is a known phenomenon, when associated with GIST it becomes even more common, with 11 cases reported up to now [11,18,19,22,[41][42][43]. In general it can be stated that in neurofibromatosis the appearance of an associated tumour increases the probability of a subsequently occurring neoplasm.…”

“…Experts of the field agree that neurofibromatosis-associated GIST is an entity separate from sporadic GIST [11][12][13][14][17][18][19][20][21]. A close association between the two conditions is indicated by the fact that GIST develops in 7% of patients with neurofibromatosis; this is higher by orders of magnitude than in the general population where the prevalence of GIST is 0.013% [9].…”

“…In the 'imatinib era' the average survival has increased from 1 year to 4.5 to 5 years. In patients with neurofibromatosis most authors consider imatinib as ineffective or at least questions its efficiency [3,5,11,12,14,17,19]. Factual data are available only on the basis of a few case reports.…”