A network of cancer genes with co-occurring and anti-co-occurring mutations

Abstract

Certain cancer genes contribute to tumorigenesis in a manner of either co-occurring or mutually exclusive (anti-co-occurring) mutations; however, the global picture of when, where and how these functional interactions occur remains unclear. This study presents a systems biology approach for this purpose. After applying this method to cancer gene mutation data generated from large-scale and whole genome sequencing of cancer samples, a network of cancer genes with co-occurring and anti-co-occurring mutations was constructed. Analysis of this network revealed that genes with co-occurring mutations prefer direct signaling transductions and that the interaction relations among cancer genes in the network are related with their functional similarity. It was also revealed that genes with co-occurring mutations tend to have similar mutation frequencies, whereas genes with anti-co-occurring mutations tend to have different mutation frequencies. Moreover, genes with more exons tend to have more co-occurring mutations with other genes, and genes having lower local coherent network structures tend to have higher mutation frequency. The network showed two complementary modules that have distinct functions and have different roles in tumorigenesis. This study presented a framework for the analysis of cancer genome sequencing outputs. The presented data and uncovered patterns are helpful for understanding the contribution of gene mutations to tumorigenesis and valuable in the identification of key biomarkers and drug targets for cancer.

Figure 1. Network of cancer genes with co-occurring and anti-co-occurring mutations (CCA network).

Each node represents one cancer gene. Genes connected by gray links represent co-occurring mutations. Genes connected by purple links represent anti-co-occurring mutations. The CCA network has two modules. Nodes in module one are red and nodes in module two are green.

Figure 2. (A) Significance of cancer genes with co-occurring mutations existing in the same signaling pathways.

The red arrow indicates the real number of cancer gene pairs that exist in the same pathway. The curve is the distribution of the random number of cancer gene pairs that exist in the same pathway. (B) Distribution of number of activation and repression signals among cancer gene pairs with co-occurring mutations. The red circle (pointed by a red arrow) indicates the real number of activation signals and repression signals that exist among the cancer gene pairs in the human signaling network. The heatmap indicates the union distribution of the random number of activation signals and repression signals that exist among the cancer gene pairs in the human signaling network. (C) Correlation between the distance of cancer genes in the CCA network and their expression similarity.

Figure 3. Comparison of absolute differences of mutation frequency (AD) among genes with co-occurring mutations, genes with anti-co-occurring mutations, and random gene pairs.

(A) Comparison of AD values for genes with co-occurring mutations (red) and genes with anti-co-occurring mutations (green). (B) Comparison of median AD values for genes with co-occurring mutations (red arrow) and the distribution of the median values for 5,000 random groups of genes with co-occurring mutations. (C) Comparison of median AD values for genes with anti-co-occurring mutations (green arrow) and the distribution of the median AD values for 5,000 random groups of genes with anti-co-occurring mutations.

Figure 4. Cellular illustration of the enriched cellular components, molecular functions and biological processes of Module One and Module Two obtained by DAVID Bioinformatics .

Module One (words with red color) is enriched in the membrane and nucleus and Module Two (words with yellow color) is enriched in the intracellular space. The enriched functions and biological processes of each module are also plotted in the corresponding locations.

Figure 5. (A) Distribution of cancer gene mutations of the 22 cancer samples from Sjoblom et al. ' study in two modules of the CCA network.

The x axis represents the number (M) of samples that have at least one mutation in Module Two. The y axis represents the number (N) of samples that have mutations only in Module Two. The red circle (pointed by a red arrow) indicates the real number of M and N. The heatmap indicates the union distribution of the random number of M and N and its color represents the probability density. (B) Comparison of mutation frequency for genes in Module One and genes in Module Two.