Analysis of pathway mutation profiles highlights collaboration between cancer-associated superpathways

Abstract

The biological interpretation of the complexity of cancer somatic mutation profiles is a major challenge in current cancer research. It has been suggested that mutations in multiple genes that participate in different pathways are collaborative in conferring growth advantage to tumor cells. Here, we propose a powerful pathway-based approach to study the functional collaboration of gene mutations in carcinogenesis. We successfully identify many pairs of significantly comutated pathways for a large-scale somatic mutation profile of lung adenocarcinoma. We find that the coordinated pathway pairs detected by comutations are also likely to be coaltered by other molecular changes, such as alterations in multifunctional genes in cancer. Then, we cluster comutated pathways into comutated superpathways and show that the derived superpathways also tend to be significantly coaltered by DNA copy number alterations. Our results support the hypothesis that comprehensive cooperation among a few basic functions is required for inducing cancer. The results also suggest biologically plausible models for understanding the heterogeneous mechanisms of cancers. Finally, we suggest an approach to identify candidate cancer genes from the derived comutated pathways. Together, our results provide guidelines to distill the pathway collaboration in carcinogenesis from the complexity of cancer somatic mutation profiles.

Discovery of co-occurring driver pathways in cancer

“…They found that some of them (such as the RAS and TP53 blocks in central nervous system, pancreas, skin, and blood tumors) would collaboratively promote cancer signaling and foster tumorigenesis. Using 18 pathways enriched with mutations in lung adenocarcinoma [8], Gu et al investigated pathway cooperation in cancer cells in terms of superpathways, which are clusters of co-disrupted pathways whose significance is tested by the hypergeometric model [25]. More recently, Gu et al devised a heuristic approach to detect cooperative functional modules in the glioblastoma multiforme (GBM) altered network which is obtained by mapping mutated genes onto a protein interaction network from the Pathway Commons database, and several pairs of significantly co-altered modules were identified which are involved in the main pathways known to be perturbed in GBM [26].…”

Personalized Pathway Enrichment Map of Putative Cancer Genes from Next Generation Sequencing Data

“…For example, Gu et al [9] analyzed the co-mutation profile of pathways in the same lung adenocarcinomas data as we used here. However, without appropriate adjustment of gene length, several pathways that are known to harbor long genes were included in their co-mutated pathway network, such as axon guidance, long-term potentiation, and long-term depression [9]. These pathways function in neuro- and brain-systems, but there is rare evidence showing their functions related to cancer.…”

“…A 2×2 contingency table was subsequently formulated, and Fisher's exact test was performed to indicate whether the mutation profiles of the two pathways were correlated. Of note, unlike the previous studies which typically counted all pathways that were involved [9], here we only included the significantly enriched pathways identified by our weighted resampling method, as the mutation events in other pathways could be raised by chance.…”

“…The Gene Ontology (GO) enrichment test is then performed based on the estimated probability for each transcript/gene. Notably, the gene length bias appears in many aspects of pathway-related analysis, such as pathway crosstalk within each sample and pathway co-mutation profile across multiple samples [9]. Appropriate adjustment could warrant the accuracy of these analyses.…”

CDPath: Cooperative Driver Pathways Discovery Using Integer Linear Programming and Markov Clustering

“…By identifying oncogenesignaling blocks from integrated human signaling network, Cui et al [17] found that some blocks (such as the RAS and TP53) collaboratively promote cancer signaling and tumorigenesis. Gu et al [18] uncovered pathway cooperation in cancer cells in significantly co-disrupted pathways using 18 pathways enriched with mutations in lung adenocarcinoma. Gu et al [19] further identified cooperative functional modules in the glioblastoma multiforme (GBM) altered network by mapping mutated genes onto a protein interaction network.…”