Familial gastrointestinal stromal tumours with germline mutation of the kit gene

TLDR: Familial gastrointestinal stromal tumours with germline mutation of the KIT gene is reported: affected members all have a KIT mutation occurring between the transmembrane and tyrosine kinase domains, which is also the region where mutations have been found in solitary GISTs

Abstract: nature genetics volume 19 august 1998 323 Gastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour of the human gastrointestinal tract. Most GISTs are solitary, and gain-offunction mutations of the KIT protooncogene have been found in these tumours1. We report here a family with multiple GISTs: affected members all have a KIT mutation occurring between the transmembrane and tyrosine kinase domains, which is also the region where mutations have been found in solitary GISTs (ref. 1). The KIT mutation in this family was detected not only in tumours but also in leukocytes, indicating that GISTs constitute a familial cancer syndrome2. Development of multiple GISTs was found in a 60-year-old Japanese woman (Fig. 1a, case 5). Her nephew (case 10) also suffered from multiple benign GISTs. Analysis of the family pedigree revealed many family members suffering from symptoms attributable to development of multiple GISTs (Fig. 1a), including case 9 (a niece of case 5) who underwent surgery for benign and malignant GISTs. The benign GISTs obtained from cases 5, 9 and 10, and the malignant GIST from case 9, all expressed the KIT protein (Fig. 1b–e). DNA was extracted from paraffin-embedded specimens of the tumours3, and the mutation was investigated using single-strand conformation polymorphism analysis4 (SSCP). SSCP of tumours from cases 5 and 10 showed wild-type and mutant bands at exon 11 (Fig. 1f). Direct sequencing of the mutant bands of exon 11 showed deletion of one of two consecutive valine residues (codon 559 and 560, GTTGTT) which are located between the transmembrane and tyrosine kinase domains. Unfortunately, DNA samples suitable for SSCP and direct sequencing were not obtained from tumours of case 9. Next, we obtained DNA from peripheral leukocytes of cases 5 and 10 and their family members. The valine deletion was detected in leukocyte DNA from cases 5, 10 and 15, but not in DNA from other family members. Case 15 is 22 years old and has so far had no abdominal symptoms. We investigated the function of the mutant KIT protein by introducing an analogous mutation into mouse Kit cDNA and transfecting it into the interleukin-3 (IL-3)-dependent Ba/F3 mouse lymphoid cell line1,5–7. Evidence was found for the constitutive phosphorylation and kinase Familial gastrointestinal stromal tumours with germline mutation of the KIT gene