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

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.Hum Mutat 32:1–8, 2011. © 2011 Wiley-Liss, Inc.