High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors
- 7 July 2009
- journal article
- research article
- Published by Wiley in Genes, Chromosomes and Cancer
- Vol. 48 (10), 886-896
- https://doi.org/10.1002/gcc.20689
Abstract
Gastrointestinal stromal tumors (GISTs) generally harbor activating mutations in KIT or platelet‐derived growth facter receptor (PDGFRA). Mutations in these receptor tyrosine kinases lead to dysregulation of downstream signaling pathways that contribute to GIST pathogenesis. GISTs with KIT or PDGFRA mutations also undergo secondary cytogenetic alterations that may indicate the involvement of additional genes important in tumor progression. Approximately 10–15% of adult and 85% of pediatric GISTs do not have mutations in KIT or in PDGFRA. Most mutant adult GISTs display large‐scale genomic alterations, but little is known about the mutation‐negative tumors. Using genome‐wide DNA arrays, we investigated genomic imbalances in a set of 31 GISTs, including 10 KIT/PDGFRA mutation‐negative tumors from nine adults and one pediatric case and 21 mutant tumors. Although all 21 mutant GISTs exhibited multiple copy number aberrations, notably losses, eight of the 10 KIT/PDGFRA mutation‐negative GISTs exhibited few or no genomic alterations. One KIT/PDGFRA mutation‐negative tumor exhibiting numerous genomic changes was found to harbor an alternate activating mutation, in the serine‐threonine kinase BRAF. The only other mutation‐negative GIST with significant chromosomal imbalances was a recurrent metastatic tumor found to harbor a homozygous deletion in chromosome arm 9p. Similar findings in several KIT‐mutant GISTs identified a minimal overlapping region of deletion of ∼0.28 Mbp in 9p21.3 that includes only the CDKN2A/2B genes, which encode inhibitors of cell‐cycle kinases. These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs.Keywords
This publication has 41 references indexed in Scilit:
- The insulin-like growth factor system as a potential therapeutic target in gastrointestinal stromal tumors.Cell Cycle, 2008
- Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): Early results of RTOG 0132/ACRIN 6665Journal of Surgical Oncology, 2008
- Novel V600E BRAF mutations in imatinib‐naive and imatinib‐resistant gastrointestinal stromal tumorsGenes, Chromosomes and Cancer, 2008
- Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumorsProceedings of the National Academy of Sciences of the United States of America, 2008
- Improved Detection of KIT Exon 11 Duplications in Formalin-Fixed, Paraffin-Embedded Gastrointestinal Stromal TumorsThe Journal of Molecular Diagnostics, 2007
- Early effects of imatinib mesylate on the expression of insulin‐like growth factor binding protein‐3 and positron emission tomography in patients with gastrointestinal stromal tumorCancer, 2006
- Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma GroupEuropean Journal of Cancer, 2004
- Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal TumorJournal of Clinical Oncology, 2003
- Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal TumorsThe New England Journal of Medicine, 2002
- Gain-of-Function Mutations of c- kit in Human Gastrointestinal Stromal TumorsScience, 1998