A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations

Yiqun Zhang; Patrick Kwok-Shing Ng; Melanie Kucherlapati; Fengju Chen; Yuexin Liu; Yiu Huen Tsang; Guillermo de Velasco; Kang Jin Jeong; Rehan Akbani; Angela Hadjipanayis; Angeliki Pantazi; Christopher A Bristow; Eunjung Lee; Harshad S Mahadeshwar; Jiabin Tang; Jianhua Zhang; Lixing Yang; Sahil Seth; Semin Lee; Xiaojia Ren; Xingzhi Song; Huandong Sun; Jonathan Seidman; Lovelace J Luquette; Ruibin Xi; Lynda Chin; Alexei Protopopov; Thomas F Westbrook; Carl Simon Shelley; Toni K Choueiri; Michael Ittmann; Carter Van Waes; John N Weinstein; Han Liang; Elizabeth P Henske; Andrew K Godwin; Peter J Park; Raju Kucherlapati; Kenneth L Scott; Gordon B Mills; David J Kwiatkowski; Chad J Creighton

doi:10.1016/j.ccell.2017.04.013

A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations

Cancer Cell. 2017 Jun 12;31(6):820-832.e3. doi: 10.1016/j.ccell.2017.04.013. Epub 2017 May 18.

Authors

Yiqun Zhang¹, Patrick Kwok-Shing Ng², Melanie Kucherlapati³, Fengju Chen¹, Yuexin Liu⁴, Yiu Huen Tsang⁵, Guillermo de Velasco⁶, Kang Jin Jeong⁷, Rehan Akbani⁴, Angela Hadjipanayis³, Angeliki Pantazi⁸, Christopher A Bristow⁹, Eunjung Lee³, Harshad S Mahadeshwar⁹, Jiabin Tang⁹, Jianhua Zhang⁹, Lixing Yang¹⁰, Sahil Seth⁹, Semin Lee¹⁰, Xiaojia Ren⁸, Xingzhi Song⁹, Huandong Sun⁹, Jonathan Seidman¹¹, Lovelace J Luquette¹⁰, Ruibin Xi¹⁰, Lynda Chin¹², Alexei Protopopov¹³, Thomas F Westbrook¹⁴, Carl Simon Shelley¹⁵, Toni K Choueiri¹⁶, Michael Ittmann¹⁷, Carter Van Waes¹⁸, John N Weinstein⁴, Han Liang¹⁹, Elizabeth P Henske²⁰, Andrew K Godwin²¹, Peter J Park²², Raju Kucherlapati³, Kenneth L Scott⁵, Gordon B Mills²³, David J Kwiatkowski²⁴, Chad J Creighton²⁵

Affiliations

¹ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁴ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, University Hospital 12 de Octubre, Madrid 28041, Spain.
⁷ Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
⁸ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; KEW Inc., Cambridge, MA 02139, USA.
⁹ Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology, Harvard University Cambridge, Cambridge, MA 02142, USA.
¹³ Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; KEW Inc., Cambridge, MA 02139, USA.
¹⁴ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁷ Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁸ Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁹ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
²⁰ The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology, Harvard University, Cambridge, MA 02142, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
²¹ Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
²² Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
²³ Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: gmills@mdanderson.org.
²⁴ The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology, Harvard University, Cambridge, MA 02142, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: dkwiatkowski@rics.bwh.harvard.edu.
²⁵ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: creighto@bcm.edu.

Abstract

Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11,219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.

Keywords: PI3K/AKT/mTOR pathway; The Cancer Genome Atlas; integrative genomics analysis; pan-cancer analysis; proteomics; reverse-phase protein arrays.

MeSH terms

Databases, Genetic
Gene Expression Profiling
Humans
Mutation
Neoplasms / genetics*
Neoplasms / metabolism
Phosphatidylinositol 3-Kinases / metabolism*
Proteogenomics*
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction
Survival Analysis
TOR Serine-Threonine Kinases / metabolism*

Substances

MTOR protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases

Abstract

MeSH terms

Substances

Grants and funding