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. 2012 Jul 18;487(7407):330-7.
doi: 10.1038/nature11252.

Comprehensive Molecular Characterization of Human Colon and Rectal Cancer

Free PMC article

Comprehensive Molecular Characterization of Human Colon and Rectal Cancer

Cancer Genome Atlas Network. Nature. .
Free PMC article


To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.


Figure 1
Figure 1. Mutation frequencies in human CRC
A. Mutation frequencies in each of the tumors. Note a clear separation of hypermutated and non-hypermutated samples. Inset: Mutations in mismatch repair genes and POLE among the hypermutated samples. The order of the samples is the same as in Figure 1A. B. Significantly mutated genes in non-hypermutated and hypermutated tumors. Blue bars represent genes identified by MutSig and genes in black bars are identified by manual examination of sequence data.
Figure 2
Figure 2. Integrative analysis of genomic changes in 195 CRC tumors
Hypermutated tumors have near diploid genomes and are highly enriched for hypermethylation, CIMP expression phenotype, and BRAF V600E mutations. Non-hypermutated tumors originating from different sites are virtually indistinguishable from each other based on their copy-number alteration patterns, DNA methylation, or gene expression patterns. Copy-number changes of the 22 autosomes are shown in shades of red for copy-number gains and shades of blue for copy-number losses.
Figure 3
Figure 3. Copy number changes and structural aberrations in CRC
A. Focal amplification of 11p15.5. Segmented DNA copy-number data from SNP arrays and low pass whole genome sequencing are shown. Each row represents a patient; amplified regions are shown in red. B. Correlation of expression levels with copy number changes for IGF2 and miR-483. C. IGF2 amplification and over-expression are mutually exclusive of alterations in PI3K signaling genes. D. Recurrent NAV2-TCF7L2 fusions. The structure of the two genes, locations of the breakpoints leading to the translocation and circular representations of all rearrangements in tumors with a fusion are shown. The red line lines represent the NAV2-TCF7L2 fusions, black lines indicate other rearrangements. The inner ring represents copy-number changes (blue = loss, pink = gain).
Figure 4
Figure 4. Diversity and frequency of genetic changes leading to deregulation of signaling pathways in CRC
Non-hypermuated (n = 165) and hypermutated (n = 30) samples with complete data were analyzed separately. Alterations are defined by somatic mutations, homozygous deletions, high-level, focal amplifications, and, in some cases, by significant up- or down-regulation of gene expression (IGF2, FZD10, SMAD4). Alteration frequencies are expressed as a percentage of all cases; activated genes are red and inactivated genes are blue. The bottom panel shows for each sample if at least one gene in each of the five pathways is altered.
Figure 5
Figure 5. Integrative analyses of multiple data sets
A. Clustering of genes and pathways affected in colon and rectum tumors deduced by PARADIGM analysis. Blue = under-expressed relative to normal and red = overexpressed relative to normal. Some of the pathways deduced by this method are shown on the right. B. Gene expression signatures and SCNAs associated with tumor aggression. Molecular signatures (rows) that show statistically significant association with tumor aggressiveness according to selected clinical assays (columns) are displayed in color, with red indicating markers of tumor aggressiveness, and blue the markers of less aggressive tumors. Significance is based on the combined p-value from the weighted Fisher’s method, corrected for multiple testing. Color intensity and score is in accordance with the strength of an individual clinical-molecular association, and is proportional to log10(p), where p is p-value for that association. To limit the vertical extent of the figure, gene expression signatures are restricted to combined p-value p<10−9, SCNAs to p<10−7 and features are shown only if they are also significant in the subset of non-MSI-H samples (the analysis was performed separately on the full data as well as on the MSI-H and non-MSI-H subgroups).

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