Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor
Open Access
- 26 November 2007
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 122 (3), 711-718
- https://doi.org/10.1002/ijc.23137
Abstract
Germâline mutations in the KIT receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). There is limited information from large kindreds regarding median age at diagnosis, detailed histopathology, clinical effects of imatinib therapy and chromosomal abnormalities of the KIT gene. We identified a large kindred with GIST. Each family member was interviewed and appropriate medical records and radiographic imaging were obtained. Archival tumor tissue was obtained to confirm diagnosis, extract genomic DNA and perform fluorescent in situ hybridization cytogenetics of the KIT gene. Fifteen of 79 individuals with GIST were identified in this kindred. There were 8 males, the mean age at diagnosis was 53.9 (range 45â71) years. Histopathology revealed microscopic proliferation and nodularity in the myenteric plexus, spindled morphology, diffuse Kit but variable CD34 staining and low mitotic rates in the setting of metastatic disease. A deletion of codon 579 in exon 11 of the KIT gene was identified in tumor and normal tissue of this family. Mutation and cytogenetic analysis revealed homozygous loss of the wildâtype KIT sequence in tumor from one individual. Four of 4 individuals treated with imatinib are alive and without progression while 9 of 11 individuals not treated with imatinib are deceased. This study describes a kindred with a propensity to develop GIST in an autosomal dominant pattern. Germâline deletion of KIT codon 579 in GIST is associated with clinical benefit from imatinib, limited utility of mitoses to predict malignant potential, and a novel homozygous deletion of this codon in one individual.Keywords
This publication has 41 references indexed in Scilit:
- Effects of screening for breast cancer on its age-incidence relationships and familial riskInternational Journal of Cancer, 2005
- Gastrointestinal stromal tumors: Clinical profile, pathogenesis, treatment strategies and prognosisJournal of Gastroenterology and Hepatology, 2005
- About the presence of interstitial cells of Cajal outside the musculature of the gastrointestinal tractJournal of Cellular and Molecular Medicine, 2005
- Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate eraCancer, 2005
- Novelc-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentationAmerican Journal of Medical Genetics Part A, 2004
- Biological significance of chromosomal imbalance aberrations in gastrointestinal stromal tumorsJournal of Biomedical Science, 2004
- Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal TumorJournal of Clinical Oncology, 2003
- Polyclonal nature of diffuse proliferation of interstitial cells of Cajal in patients with familial and multiple gastrointestinal stromal tumoursGut, 2002
- Gain-of-Function Mutations of c- kit in Human Gastrointestinal Stromal TumorsScience, 1998
- Prognostic implications of patterns of failure for gastrointestinal leiomyosarcomasCancer, 1992