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. 2012;7(7):e42001.
doi: 10.1371/journal.pone.0042001. Epub 2012 Jul 31.

A Comprehensive Characterization of Genome-Wide Copy Number Aberrations in Colorectal Cancer Reveals Novel Oncogenes and Patterns of Alterations

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Free PMC article

A Comprehensive Characterization of Genome-Wide Copy Number Aberrations in Colorectal Cancer Reveals Novel Oncogenes and Patterns of Alterations

Tao Xie et al. PLoS One. .
Free PMC article

Abstract

To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.

Conflict of interest statement

Competing Interests: TX, JL, KW, MM, SW, PR and JGH are or were employed by Pfizer Inc. However, this does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. The authors have declared that no other competing interests exist.

Figures

Figure 1
Figure 1. Summary of copy number aberrations detected in 269 MSS stage II/III colon cancer samples.
(A) Frequencies of copy number gain (above axis, blue) and copy number loss (below axis, red) across the human genome. (B) Significance of focal amplifications detected by GISTIC 2.0. Chromosome positions were indicated along the y axis with centromere positions indicated by dotted lines. The ten most significant GISTIC peaks are shown in red text. Additional GISTIC peaks encoding established oncogenes are in black text. Details for all GISTIC peaks are provided in Table S3.
Figure 2
Figure 2. Focal amplification of genomic loci in selected stage II/III colon cancer samples.
(A–H) Copy number plots for the entire genome arranged in chromosomal order from the short arm of chromosome 1 (1pter) to the long arm of chromosome X (Xqter) for 8 independent tumor samples. Amplicons of particular interest are highlighted with arrows, along with established oncogenes. Details regarding all amplicons and GISTIC peaks are in Table S3.
Figure 3
Figure 3. Boxplots for WNK1 (A) and HNF4A’s (B) mRNA expression grouped by CNA status.
Tumor samples were categorized by their CNA status (deletion, loss, normal, gain, amplification) for the indicated gene. The panels show the expression level by category for each probeset from the ALMAC platform (see Materials and Methods) representing the specific gene. The values were centered for each probeset; categories are plotted if there was at least one sample in it.
Figure 4
Figure 4. Unsupervised hierarchical clustering analysis based of genome-wide copy number data.
(A) Three major clusters. The right-hand annotation indicates, in order, the BRAFm (in yellow, BRAF mutants; in blue, BRAF wild-types), KRASm (mutants in green), and BRAFm-like (in green, BRAFm-like; in red, non-BRAFm-like). Purple color indicates missing values. (B) Genome-wide frequency plot of copy number gain (above axis, blue) and copy number loss (below axis, red) across three major clusters.
Figure 5
Figure 5. Pair-wise DNA/DNA correlations reveal significant associations between unlinked loci.
(A) Pair-wise correlations computed from gene copy number are ordered by chromosomal positions through the genome on the X and Y axes, with red indicating a positive correlation and blue indicating a negative correlation. The red diagonal represents the correlation of a gene with itself. The lower right and upper left portions of the graph represent mirror images of each other showing the copy number correlations of unlinked loci. (B) Log/log plots for significant gene/gene correlations (|R|≥0.3).

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Grant support

This work was supported in part by a grant from the Swiss National Science Foundation (SNF 320030_135421) and Foundation Medic and a grant of the Krebsforschung Schweiz (KFS 02697-08-2010) to AR and MD. ST is a senior clinical investigator of the Fund for Scientific Research Flanders and has received research grants from the Belgian Federation Against Cancer and from the Belgian National Cancer Plan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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