title: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Perry
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Adam
authors.initials: A
authors.lastname: Kiezun
authors.affiliation: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215;
authors.forename: Peter
authors.initials: P
authors.lastname: Tonzi
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Sylvan C
authors.initials: SC
authors.lastname: Baca
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Ami S
authors.initials: AS
authors.lastname: Bhatt
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Esther
authors.initials: E
authors.lastname: Rheinbay
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Elena
authors.initials: E
authors.lastname: Helman
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: David S
authors.initials: DS
authors.lastname: DeLuca
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Lauren
authors.initials: L
authors.lastname: Ambrogio
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Andrey
authors.initials: A
authors.lastname: Sivachenko
authors.affiliation: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215; Department of Pediatrics.
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Medicine.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.affiliation: Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain;
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.affiliation: Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain;
authors.forename: Carmen
authors.initials: C
authors.lastname: de Torres
authors.affiliation: Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain;
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lavarino
authors.affiliation: Department of Pediatric Oncology, Centro Infantil Boldrini, Campinas, 13083-210, Brazil; Center for Pediatric Research.
authors.forename: Simone
authors.initials: S
authors.lastname: Dos Santos Aguiar
authors.affiliation: Department of Pediatric Oncology, Centro Infantil Boldrini, Campinas, 13083-210, Brazil; Medical Genetics Department, Faculty of Medical Sciences, State University of Campinas, Campinas 13083-887, Brazil;
authors.forename: Jose Andres
authors.initials: JA
authors.lastname: Yunes
authors.affiliation: Department of Pediatric Oncology, Centro Infantil Boldrini, Campinas, 13083-210, Brazil;
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Brandalise
authors.affiliation: Subdirection of Basic Research, National Institute of Genomic Medicine, 14610, Mexico City, Mexico;
authors.forename: Gabriela Elisa
authors.initials: GE
authors.lastname: Mercado-Celis
authors.affiliation: Subdirection of Basic Research, National Institute of Genomic Medicine, 14610, Mexico City, Mexico;
authors.forename: Jorge
authors.initials: J
authors.lastname: Melendez-Zajgla
authors.affiliation: Department of Oncology, National Institute of Pediatrics, 04530, Mexico City, Mexico;
authors.forename: Rocío
authors.initials: R
authors.lastname: Cárdenas-Cardós
authors.affiliation: Department of Oncology, National Institute of Pediatrics, 04530, Mexico City, Mexico;
authors.forename: Liliana
authors.initials: L
authors.lastname: Velasco-Hidalgo
authors.affiliation: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215; Department of Pediatrics.
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Medicine.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215; Department of Pediatrics.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Systems Biology, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Pediatrics, Howard Hughes Medical Institute, Chevy Chase, MD 20815.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215; Department of Pediatrics, Howard Hughes Medical Institute, Chevy Chase, MD 20815 stuart_orkin@dfci.harvard.edu gadgetz@broadinstitute.org kjaneway@partners.org.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Pathology, Harvard Medical School, Boston, MA 02115; stuart_orkin@dfci.harvard.edu gadgetz@broadinstitute.org kjaneway@partners.org.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215; Department of Pediatrics, stuart_orkin@dfci.harvard.edu gadgetz@broadinstitute.org kjaneway@partners.org.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018740:Genetic Heterogeneity; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C546842:MTOR protein, human
keywords: PI3K; TP53; genomics; mTOR; osteosarcoma