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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1419260111

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

Publication TypeJournal Article
Year of Publication2014
AuthorsPerry, JA, Kiezun, A, Tonzi, P, Van Allen, EM, Carter, SL, Baca, SC, Cowley, GS, Bhatt, AS, Rheinbay, E, Pedamallu, CSekhar, Helman, E, Taylor-Weiner, A, McKenna, A, DeLuca, DS, Lawrence, MS, Ambrogio, L, Sougnez, C, Sivachenko, A, Walensky, LD, Wagle, N, Mora, J, de Torres, C, Lavarino, C, Aguiar, SDos Santos, Yunes, JAndres, Brandalise, SRegina, Mercado-Celis, GElisa, Melendez-Zajgla, J, Cárdenas-Cardós, R, Velasco-Hidalgo, L, Roberts, CWM, Garraway, LA, Rodriguez-Galindo, C, Gabriel, SB, Lander, ES, Golub, TR, Orkin, SH, Getz, G, Janeway, KA
JournalProc Natl Acad Sci U S A
Volume111
Issue51
PagesE5564-73
Date Published2014 Dec 23
ISSN1091-6490
KeywordsBone Neoplasms, Cell Line, Tumor, Cell Proliferation, Genetic Heterogeneity, Genome, Human, Germ-Line Mutation, Humans, Osteosarcoma, Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Tumor Suppressor Protein p53
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.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=25512523
DOI10.1073/pnas.1419260111
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25512523?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID25512523
PubMed Central IDPMC4280630
Grant ListU01 CA105423 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
U01CA105423 / CA / NCI NIH HHS / United States