Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma
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Perry-2014-Complementary genomi.pdf
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1.39 MB
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Author(s)
Lander, Eric Steven
Date Issued
December 2014
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Perry, Jennifer A., Adam Kiezun, Peter Tonzi, Eliezer M. Van Allen, Scott L. Carter, Sylvan C. Baca, Glenn S. Cowley, et al. “Complementary Genomic Approaches Highlight the PI3K/mTOR Pathway as a Common Vulnerability in Osteosarcoma.” Proceedings of the National Academy of Sciences 111, no. 51 (December 15, 2014): E5564–E5573.
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Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1073/pnas.1419260111
