A multidimensional analysis of genes mutated in breast and colorectal cancers

Abstract

A recent study of a large number of genes in a panel of breast and colorectal cancers identified somatic mutations in 1149 genes. To identify potential biological processes affected by these genes, we examined their putative roles based on sequence similarity, membership in known functional groups and pathways, and predicted interactions with other proteins. These analyses identified functional groups and pathways that were enriched for mutated genes in both tumor types. Additionally, the results pointed to differences in molecular mechanisms that underlie breast and colorectal cancers, including various intracellular signaling and metabolic pathways. These studies provide a multidimensional framework to guide further research and help identify cellular processes critical for malignant progression and therapeutic intervention.

Figure 1.

Sequence similarity among mutated genes in breast and colorectal cancers. Each cluster represents genes that are mutated in breast (top) or colorectal cancers (bottom). Each node represents a gene that is colored according to the Cancer Mutation Prevalence Score (CaMP score), and each line represents a sequence-similarity relationship that is colored according to degree of sequence similarity. CAN-genes identified by Sjöblom et al. (2006) have a CaMP score >1 and are colored in orange and red. Clusters are named according to the predominant genes contained within each cluster, and those containing only two genes are not shown. The percentage of the total mutated genes contained within each cluster is showed in parentheses. The inset highlights local similarity within protein domains of genes in a specific cluster.

Figure 2.

General functional categorization of genes mutated in breast and colorectal cancers. Each small circle represents a mutated gene in breast or colorectal cancer and is colored according to the general functional categories shown in the legend (for details, see Methods). The entire set of circles represents all the genes mutated in each cancer type, while the interior subset is comprised of the genes with the highest CaMP Scores (the CAN-genes). The percentage of genes that belong to each functional category is shown in the legend.

Figure 3.

Interaction among proteins mutated in breast and colorectal cancers. Each node represents a mutated protein that is colored according to Cancer Mutation Prevalence (CaMP) Score, and each line represents an interaction confidence. CAN-genes identified by Sjöblom et al. (2006) have a CaMP score >1 and are colored in orange and red. The genes are placed within cellular compartments as annotated in Gene Ontology.

Figure 4.

Comparison of mutation enrichment in cellular pathways using complementary statistical approaches. Venn diagrams show the number of pathways identified from four different databases in breast (left) and colorectal cancers (right) using CaMP GSEA and Group CaMP approaches. Each circle represents one pathway and is colored according to the database it belongs to. Pathways that were enriched for mutations and which were filtered for an increase in the number of genes using the χ² test are shown in tan or pink. Blue and dark tan areas represent pathways that were excluded using the χ² filter (for additional details, see Methods).

Figure 5.

Comparison of genes annotated though different mutation enrichment classification methods. Five-way Venn diagrams (Grünbaum 1975) show the number of genes annotated through the indicated methods for breast and colorectal cancers. The “Gene Mutation Enrichment” set are the CAN-genes defined by Sjöblom et al. (2006). Each region indicates the number of genes that are detected by the different analytical methods, and is colored according to the number of methods that identify those genes. The genes detected by each classification method are listed in Supplemental Table 4, A and B.