Osteosarcoma is the most common primary bone tumor and yet there have been no substantial advances in treatment or survival in over 2 decades. We examined 59 tumor/normal pairs by whole-genome, whole-exome and RNA-Sequencing. Only TP53 was mutated at significant frequency across the 59 samples. The mean non-silent somatic mutation rate was 1.2 mutation per megabase and there were a median of 231 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the inter-tumor 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 proliferation and survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach and a genome-wide, pooled short hairpin RNA (shRNA) screen all point to the PI3K/mTOR pathway as a potential 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.
Citation Format: Adam Kiezun, Jennifer Perry, Peter Tonzi, Eliezer Van Allen, Scott L. Carter, Sylvan Baca, Ami Bhatt, Michael Lawrence, Loren Walensky, Nikhil Wagle, Jaume Mora, Carmen deTorres, Cinzia Lavarino, Liliana Velasco-Hidalgo, Rocio Cardenas-Cardos, Simone dos Santos Aguiar, Jose A. Yunes, Gabriela Mercado, Jorge Melendez-Zajgla, Charles Roberts, Levi Garraway, Carlos Rodriguez-Galindo, Todd Golub, Stuart Orkin, Gad Getz, Katherine Janeway. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A41.