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Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor
Eric P Kleinbaum1, Alexander J F Lazar, Elena Tamborini
1Department of Sarcoma Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
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.
Insights
A large family study identified a germ-line deletion in the KIT gene in individuals with gastrointestinal stromal tumors (GIST). This mutation is linked to better outcomes with imatinib therapy, highlighting its importance in GIST development and treatment.
Area of Science:
- Oncology
- Genetics
- Gastroenterology
Background:
- Germ-line mutations in the KIT receptor tyrosine kinase gene are associated with familial gastrointestinal stromal tumor (GIST).
- Limited data exists on large kindreds concerning GIST diagnosis, histopathology, imatinib response, and KIT gene abnormalities.
Purpose of the Study:
- To investigate a large kindred with a propensity for GIST.
- To detail the clinical, histopathological, and genetic features of GIST within this family.
- To evaluate the impact of imatinib therapy on affected individuals.
Main Methods:
- Family interviews, medical record review, and radiographic imaging.
- Analysis of archival tumor tissue for diagnosis confirmation, genomic DNA extraction, and KIT gene fluorescent in situ hybridization (FISH) cytogenetics.
- Mutation analysis of the KIT gene.
Main Results:
- Fifteen of 79 individuals in the kindred had GIST, with a mean age at diagnosis of 53.9 years.
- Histopathology showed specific features including myenteric plexus involvement and variable CD34 staining. A deletion of codon 579 in exon 11 of the KIT gene was identified.
- Individuals treated with imatinib (4/4) showed no progression, while untreated individuals (9/11) had deceased.
Conclusions:
- The study identified an autosomal dominant pattern of GIST inheritance in a large kindred.
- Germ-line deletion of KIT codon 579 in GIST is associated with a positive clinical response to imatinib.
- Mitotic rate has limited utility in predicting malignant potential in this context, and a novel homozygous deletion of KIT codon 579 was observed in one patient.
