A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations

Cancer Cell. 2017 Jun 12;31(6):820-832.e3. doi: 10.1016/j.ccell.2017.04.013. Epub 2017 May 18.

Abstract

Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11,219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.

Keywords: PI3K/AKT/mTOR pathway; The Cancer Genome Atlas; integrative genomics analysis; pan-cancer analysis; proteomics; reverse-phase protein arrays.

Publication types

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

MeSH terms

  • Databases, Genetic
  • Gene Expression Profiling
  • Humans
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proteogenomics*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Survival Analysis
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt