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.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.2 K.G
In addition to the well-known targets ERBB2 and MYC, we identified novel recurrent high-level amplifications of TOX3 (16q) and CCND2 (12p) in colorectal cancers (CRCs)
All TOX3 amplifications were focal, and the event was associated with increased gene expression, suggesting that TOX3 may be targeted by amplification in a small subset of CRCs
Summary
Colorectal cancers (CRC) can be classified into four biologically distinct and clinically relevant consensus molecular subtypes (CMS) based on their global gene expression patterns [1]. Little is in general known about the genetic basis for the distinct gene expression-based subtypes. Chromosomal instability is an integral part of canonical CRC pathogenesis, and the majority of CRCs are characterized by a large burden of CNAs. Chromosomal instability is associated with poor patient prognosis [2] and resistance to multiple drugs [3]. The chromosome instability phenotype is clearly distinct from the MSI phenotype, which is characterized by frequent singlenucleotide variants and small insertions and deletions, there is a large extent of molecular heterogeneity among chromosomally instable tumors
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