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

Nat Genet. 2015 Feb;47(2):106-14. doi: 10.1038/ng.3168. Epub 2014 Dec 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms*
  • Computational Biology / methods*
  • Databases, Genetic
  • Gene Regulatory Networks / genetics*
  • Genome / genetics*
  • Humans
  • Multiprotein Complexes / genetics
  • Mutation
  • Neoplasms / diagnosis
  • Neoplasms / genetics*
  • Signal Transduction / genetics*

Substances

  • Multiprotein Complexes