Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma

Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5564-73. doi: 10.1073/pnas.1419260111. Epub 2014 Dec 15.

Abstract

Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo.

Keywords: PI3K; TP53; genomics; mTOR; osteosarcoma.

Publication types

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

MeSH terms

  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Genetic Heterogeneity
  • Genome, Human*
  • Germ-Line Mutation
  • Humans
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism*
  • Osteosarcoma / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MTOR protein, human
  • TOR Serine-Threonine Kinases

Associated data

  • dbGaP/PHS000694.V1.P1
  • dbGaP/PHS000699.V1.P1