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

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

Author information

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

PMID:
28528867
PMCID:
PMC5502825
DOI:
10.1016/j.ccell.2017.04.013
[Indexed for MEDLINE]
Free PMC Article

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