Leiserson, Mark D.M.Vandin, FabioWu, Hsin-TaDobson, Jason R.Eldridge, Jonathan V.Thomas, Jacob L.Papoutsaki, AlexandraKim, YounhunNiu, BeifangMcLellan, MichaelLawrence, Michael S.Gonzalez-Perez, AbelTamborero, DavidCheng, YuweiRyslik, Gregory A.Lopez-Bigas, NuriaGetz, GadDing, LiRaphael, Benjamin J.2015-09-012014Leiserson, M. D., F. Vandin, H. Wu, J. R. Dobson, J. V. Eldridge, J. L. Thomas, A. Papoutsaki, et al. 2014. “Pan-Cancer Network Analysis Identifies Combinations of Rare Somatic Mutations across Pathways and Protein Complexes.” Nature genetics 47 (2): 106-114. doi:10.1038/ng.3168. http://dx.doi.org/10.1038/ng.3168.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:21462211Cancers exhibit extensive mutational heterogeneity and the resulting long tail phenomenon complicates the discovery of the genes and pathways that are significantly mutated in cancer. We perform a Pan-Cancer analysis of mutated networks in 3281 samples from 12 cancer types from The Cancer Genome Atlas (TCGA) using HotNet2, a novel algorithm to find mutated subnetworks that overcomes limitations of existing single gene and pathway/network approaches.. We identify 14 significantly mutated subnetworks that include well-known cancer signaling pathways as well as subnetworks with less characterized roles in cancer including cohesin, condensin, and others. Many of these subnetworks exhibit co-occurring mutations across samples. These subnetworks contain dozens of genes with rare somatic mutations across multiple cancers; many of these genes have additional evidence supporting a role in cancer. By illuminating these rare combinations of mutations, Pan-Cancer network analyses provide a roadmap to investigate new diagnostic and therapeutic opportunities across cancer types.en-USJournal Article2015-09-0110.1038/ng.3168