AMACR amplification and overexpression in primary imatinib-naïve gastrointestinal stromal tumors: a driver of cell proliferation indicating adverse prognosis

Non-random gains of chromosome 5p have been observed in clinically aggressive gastrointestinal stromal tumors, whereas the driving oncogenes on 5p remain to be characterized. We used an integrative genomic and functional approach to identify amplified oncogenes on 5p and to evaluate the relevance of...

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Bibliographic Details
Published in:Oncotarget 2014-11, Vol.5 (22), p.11588-11603
Main Authors: Li, Chien-Feng, Chen, Li-Tzong, Lan, Jui, Chou, Fong-Fu, Lin, Ching-Yih, Chen, Yen-Yang, Chen, Tzu-Ju, Li, Shau-Hsuan, Yu, Shih-Chen, Fang, Fu-Ming, Tai, Hui-Chun, Huang, Hsuan-Ying
Format: Article
Language:English
Subjects:
Azoles - chemistry
Benzamides - administration & dosage
Cell Line, Tumor
Cell Proliferation
Comparative Genomic Hybridization
Cyclin D1 - metabolism
Cyclin E - metabolism
Cyclin-Dependent Kinase 4 - metabolism
Disease-Free Survival
DNA Mutational Analysis
Flow Cytometry
G1 Phase
Gastrointestinal Stromal Tumors - drug therapy
Gene Dosage
Genotype
Humans
Imatinib Mesylate
Immunohistochemistry
In Situ Hybridization, Fluorescence
Multivariate Analysis
Oncogene Proteins - metabolism
Organoselenium Compounds - chemistry
Piperazines - administration & dosage
Predictive Value of Tests
Prognosis
Pyrimidines - administration & dosage
Racemases and Epimerases - genetics
Racemases and Epimerases - metabolism
Research Paper
RNA Interference
Treatment Outcome
Up-Regulation
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Summary:Non-random gains of chromosome 5p have been observed in clinically aggressive gastrointestinal stromal tumors, whereas the driving oncogenes on 5p remain to be characterized. We used an integrative genomic and functional approach to identify amplified oncogenes on 5p and to evaluate the relevance of AMACR amplification at 5p13.3 and its overexpression in gastrointestinal stromal tumors. Thirty-seven tumor samples, imatinib-sensitive GIST882 cell line, and imatinib-resistant GIST48 cell line were analyzed for DNA imbalances using array-based genomic profiling. Forty-one fresh tumor samples of various risk categories were enriched for pure tumor cells by laser capture microdissection and quantified for AMACR mRNA expression. AMACR-specific fluorescence in situ hybridization and immunohistochemistry were both informative in tissue microarray sections of 350 independent primary gastrointestinal stromal tumors, including 213 cases with confirmed KIT /PDGFRA genotypes. To assess the oncogenic functions of AMACR, GIST882 and GIST48 cell lines were stably silenced against their endogenous AMACR expression. In 59% of cases featuring 5p gains, two major amplicons encompassed discontinuous chromosomal regions that were differentially overrepresented in high-risk cases, including the one harboring the mRNA-upregulated AMACR gene. Gene amplification was detected in 19.7% of cases (69/350) and strongly related to protein overexpression (p
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2597