Germ-line 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 45-71) 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 wild-type 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. Germ-line 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. ' 2007 Wiley-Liss, Inc.

9527 Background: Germ-line mutations in the kit receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). We describe a large kindred with multiple individuals with GIST and describe the genotype, clinical presentation, radiographic imaging, surgical findings, imatinib-sensitivity, and histopathologic appearance. Patients and Methods: A large kindred with multiple GISTs were identified after the proband patient was referred to our institution. The history of each affected and unaffected family member was obtained in person or via telephone. A medical questionnaire was sent to family members and appropriate medical records, tumor tissue and radiographic imaging was obtained. Histopathologic specimens from four of the family members with GIST was obtained, the diagnosis confirmed and three specimens were used to sequence kit exon 9, 11, 13, 15 and 17. Results: Fifteen members were identified in this family with histopathologic diagnosis of GIST or probable GIST. Surgical findings revealed multiple tumors arising from the submucosa of the small intestine. Histopathology revealed microscopic proliferation of the myenteric plexus with areas of microscopic tumor nodularity. Four patients in this kindred were treated with imatinib and had radiographic and clinical evidence of therapeutic benefit. A deletion of codon 579 in exon 11 of the kit gene was identified in tumor and normal tissue of this family. Evaluation of one GIST revealed loss of heterozygosity in kit exon 11 suggesting a homozygous mutation or loss of the wild-type locus. Conclusion: This study describes a kindred with a propensity to develop GIST in association with hyperpigmentation and melanocytic nevi, but not dysphagia. The germline deletion of codon 579 appears to confer proliferation and nodularity of the myenteric plexus, synchronous tumors at presentation, a metastatic phenotype, and in vivo sensitivivity to imatinib therapy. No significant financial relationships to disclose.