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

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

Perry JA¹, Kiezun A², Tonzi P¹, Van Allen EM³, Carter SL², Baca SC³, Cowley GS², Bhatt AS³, Rheinbay E², Pedamallu CS³, Helman E³, Taylor-Weiner A², McKenna A², DeLuca DS², Lawrence MS², Ambrogio L², Sougnez C², Sivachenko A², Walensky LD⁴, Wagle N⁵, Mora J⁶, de Torres C⁶, Lavarino C⁶, Dos Santos Aguiar S⁷, Yunes JA⁸, Brandalise SR⁹, Mercado-Celis GE¹⁰, Melendez-Zajgla J¹⁰, Cárdenas-Cardós R¹¹, Velasco-Hidalgo L¹¹, Roberts CW⁴, Garraway LA⁵, Rodriguez-Galindo C⁴, Gabriel SB², Lander ES¹², Golub TR¹³, Orkin SH¹⁴, Getz G¹⁵, Janeway KA¹⁶.

Author information

1: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215;
2: The Broad Institute of MIT and Harvard, Cambridge, MA 02142;
3: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
4: Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215; Department of Pediatrics.
5: 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.
6: Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain;
7: Department of Pediatric Oncology, Centro Infantil Boldrini, Campinas, 13083-210, Brazil; Center for Pediatric Research.
8: 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;
9: Department of Pediatric Oncology, Centro Infantil Boldrini, Campinas, 13083-210, Brazil;
10: Subdirection of Basic Research, National Institute of Genomic Medicine, 14610, Mexico City, Mexico;
11: Department of Oncology, National Institute of Pediatrics, 04530, Mexico City, Mexico;
12: 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.
13: The Broad Institute of MIT and Harvard, Cambridge, MA 02142; Department of Pediatrics, Howard Hughes Medical Institute, Chevy Chase, MD 20815.
14: 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.
15: 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.
16: 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.

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.