Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes

Mark D.M. Leiserson, Fabio Vandin, Hsin Ta Wu, Jason R. Dobson, Jonathan V. Eldridge, Jacob L. Thomas, Alexandra Papoutsaki, Younhun Kim, Beifang Niu, Michael McLellan, Michael S. Lawrence, Abel Gonzalez-Perez, David Tamborero, Yuwei Cheng, Gregory A. Ryslik, Nuria Lopez-Bigas, Gad Getz, Li Ding, Benjamin J. Raphael

Research output: Contribution to journalArticle

371 Scopus citations

Abstract

Cancers exhibit extensive mutational heterogeneity, and the resulting long-tail phenomenon complicates the discovery of genes and pathways that are significantly mutated in cancer. We perform a pan-cancer analysis of mutated networks in 3,281 samples from 12 cancer types from The Cancer Genome Atlas (TCGA) using HotNet2, a new algorithm to find mutated subnetworks that overcomes the limitations of existing single-gene, pathway and network approaches. We identify 16 significantly mutated subnetworks that comprise 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.

Original languageEnglish (US)
Pages (from-to)106-114
Number of pages9
JournalNature Genetics
Volume47
Issue number2
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics

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    Leiserson, M. D. M., Vandin, F., Wu, H. T., Dobson, J. R., Eldridge, J. V., Thomas, J. L., Papoutsaki, A., Kim, Y., Niu, B., McLellan, M., Lawrence, M. S., Gonzalez-Perez, A., Tamborero, D., Cheng, Y., Ryslik, G. A., Lopez-Bigas, N., Getz, G., Ding, L., & Raphael, B. J. (2015). Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes. Nature Genetics, 47(2), 106-114. https://doi.org/10.1038/ng.3168