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Gene expression profiles of CMS2-epithelial/canonical colorectal cancers are largely driven by DNA copy number gains
- Source :
- Oncogene
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- About 80% of colorectal cancers (CRCs) have chromosomal instability, which is an integral part of aggressive malignancy development, but the importance of specific copy number aberrations (CNAs) in modulating gene expression, particularly within the framework of clinically relevant molecular subtypes, remains mostly elusive. We performed DNA copy number profiling of 257 stage I-IV primary CRCs and integrative gene expression analysis in 151 microsatellite stable (MSS) tumors, focusing on high-level amplifications and the effect of CNAs on the characteristics of the gene expression-based consensus molecular subtypes (CMS). The results were validated in 323 MSS tumors from TCGA. Novel recurrent high-level amplifications (≥15 additional copies) with a major impact on gene expression were found for TOX3 (16q) at 1.5% frequency, as well as for CCND2 (12p) and ANXA11 (10q) at 1% frequency, in addition to the well-known targets ERBB2 (17q) and MYC (8q). Focal amplifications with ≥15 or ≥5 additional copies of at least one of these regions were associated with a poor overall survival among patients with stage I-III MSS CRCs (multivariable hazard ratio ≥3.2, p ≤ 0.01). All high-level amplifications were focal and had a more consistent relationship with gene expression than lower amplitude and/or broad-range amplifications, suggesting specific targeting during carcinogenesis. Genome-wide, copy number driven gene expression was enriched for pathways characteristic of the CMS2-epithelial/canonical subtype, including DNA repair and cell cycle progression. Furthermore, 50% of upregulated genes in CMS2-epithelial/canonical MSS CRCs were driven by CNAs, an enrichment compared with the other CMS groups, and associated with the stronger correspondence between CNAs and gene expression in malignant epithelial cells than in the cells of the tumor microenvironment (fibroblasts, endothelial cells, leukocytes). In conclusion, we identify novel recurrent amplifications with impact on gene expression in CRC and provide the first evidence that CMS2 may have a stronger copy-number related genetic basis than subtypes more heavily influenced by gene expression signals from the tumor microenvironment. publishedVersion
- Subjects :
- Male
0301 basic medicine
Cancer Research
DNA Copy Number Variations
DNA Mutational Analysis
Gene Dosage
Biology
medicine.disease_cause
Article
03 medical and health sciences
0302 clinical medicine
Chromosome instability
Gene expression
Cancer genomics
Tumor Microenvironment
Genetics
medicine
Humans
Molecular Biology
Gene
Regulation of gene expression
Gene Expression Profiling
Gene Amplification
Microsatellite instability
medicine.disease
Colorectal cancer
Survival Analysis
Gene Expression Regulation, Neoplastic
Gene expression profiling
030104 developmental biology
Molecular Diagnostic Techniques
TOX3
030220 oncology & carcinogenesis
Cancer research
Female
Microsatellite Instability
Colorectal Neoplasms
Transcriptome
Carcinogenesis
Microsatellite Repeats
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....f8e7ae196f8a4f6946233a9117142d56