Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia

Robson, M. E., Glogowski, E., Sommer, G., Antonescu, C. R., Nafa, K., Maki, R. G., Ellis, N., Besmer, P., Brennan, M., Offit, K. (February 2004) Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res, 10 (4). pp. 1250-4. ISSN 1078-0432 (Print)1078-0432 (Linking)

DOI: 10.1158/1078-0432.ccr-03-0110


PURPOSE: Somatic mutations that result in the activation of the growth factor receptor KIT are commonly found in gastrointestinal stromal tumors (GISTs). Six families have been reported in which a germ-line mutation in KIT is associated with an autosomal dominant predisposition to the development of GISTs. Hyperpigmentation, urticaria pigmentosa, and dysphagia have been described in some, but not all, families. Preliminary correlations between the site of mutation and the clinical phenotype have been proposed, but the strength of these associations is not defined. DESIGN: A large kindred with multiple GISTs, hyperpigmentation, and dysphagia was identified after the index case presented with multiple GISTs. A germ-line mutation in KIT (W557R) was identified in an affected cousin, after which a large family meeting was held and testing offered. Clinical data were obtained by interview and, whenever possible, medical record documentation. RESULTS: To date, 19 individuals have been tested, and the mutation has been shown to cosegregate with the syndrome. The phenotypic expression, however, is variable. GISTs, often presenting as upper gastrointestinal bleeding, and hyperpigmentation are common, but not diagnosed in all documented or obligate carriers. Dysphagia is a less prevalent complaint. The diagnosis of GISTs appears to be made at a younger age in more recent generations. Metastatic disease is uncommon. CONCLUSIONS: A germ-line mutation in KIT resulting in an amino acid substitution in the juxtamembrane region is associated with a syndrome of GIST, hyperpigmentation, and dysphagia, although the prominence of each component varies.

Item Type: Paper
Uncontrolled Keywords: Age Factors Cell Membrane/metabolism Deglutition Disorders/*genetics Family Health Female Gastrointestinal Neoplasms/*genetics *Germ-Line Mutation Humans Hyperpigmentation/*genetics Male Middle Aged *Mutation Pedigree Phenotype Proto-Oncogene Proteins c-kit/*genetics Time Factors
Subjects: diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 15 February 2004
Date Deposited: 26 Oct 2016 20:59
Last Modified: 26 Oct 2016 20:59
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