Journal Article

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

Eric S. Lander, Glenn S. Cowley, Liliana Velasco-Hidalgo, Jose Andres Yunes, Gad Getz, Chandra Sekhar Pedamallu, Simone Dos Santos Aguiar, Andrey Sivachenko, Gabriela Elisa Mercado-Celis, Eliezer M. Van Allen, Michael S. Lawrence, Nikhil Wagle, Levi A. Garraway, Ami S. Bhatt, Peter Tonzi, Lauren Ambrogio, Stacey B. Gabriel, Katherine A. Janeway, Carrie Sougnez, Adam Kiezun, Carlos Rodriguez-Galindo, Todd R. Golub, Jorge Melendez-Zajgla, David S. DeLuca, Jaume Mora, Carmen de Torres, Charles W. M. Roberts, Cinzia Lavarino, Elena Helman, Amaro Taylor-Weiner, Loren D. Walensky, Aaron McKenna, Rocío Cárdenas-Cardós, Jennifer A. Perry, Silvia Regina Brandalise, Sylvan C. Baca, Stuart H. Orkin, Esther Rheinbay, Scott L. Carter

2014

Overview

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. Significance We present, to our knowledge, the first comprehensive next-generation sequencing of osteosarcoma in combination with a functional genomic screen in a genetically defined mouse model of osteosarcoma. Our data provide a strong rationale for targeting the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in osteosarcoma and a foundation for rational clinical trial design. These findings present an immediate clinical opportunity because multiple inhibitors of this pathway are currently in clinical trials.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: animal models / Biological Sciences / Bone Neoplasms - genetics / Bone Neoplasms - metabolism / Bone Neoplasms - pathology / Cell Line, Tumor / Cell Proliferation / clinical trials / Comparative analysis / Genetic Heterogeneity / Genome, Human / Genomes / Genomics / Germ-Line Mutation / Heterogeneity / high-throughput nucleotide sequencing / Humans / Mutation / Oncology / osteosarcoma / Osteosarcoma - genetics / Osteosarcoma - metabolism / Osteosarcoma - pathology / Phosphatidylinositol 3-Kinases - metabolism / PNAS Plus / Ribonucleic acid / RNA / TOR Serine-Threonine Kinases - metabolism / Tumor Suppressor Protein p53 - genetics / Tumors