TY - JOUR
T1 - A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations
AU - Zhang, Yiqun
AU - Kwok-Shing Ng, Patrick
AU - Kucherlapati, Melanie
AU - Chen, Fengju
AU - Liu, Yuexin
AU - Tsang, Yiu Huen
AU - de Velasco, Guillermo
AU - Jeong, Kang Jin
AU - Akbani, Rehan
AU - Hadjipanayis, Angela
AU - Pantazi, Angeliki
AU - Bristow, Christopher A.
AU - Lee, Eunjung
AU - Mahadeshwar, Harshad S.
AU - Tang, Jiabin
AU - Zhang, Jianhua
AU - Yang, Lixing
AU - Seth, Sahil
AU - Lee, Semin
AU - Ren, Xiaojia
AU - Song, Xingzhi
AU - Sun, Huandong
AU - Seidman, Jonathan
AU - Luquette, Lovelace J.
AU - Xi, Ruibin
AU - Chin, Lynda
AU - Protopopov, Alexei
AU - Westbrook, Thomas F.
AU - Shelley, Carl Simon
AU - Choueiri, Toni K.
AU - Ittmann, Michael
AU - Van Waes, Carter
AU - Weinstein, John N.
AU - Liang, Han
AU - Henske, Elizabeth P.
AU - Godwin, Andrew K.
AU - Park, Peter J.
AU - Kucherlapati, Raju
AU - Scott, Kenneth L.
AU - Mills, Gordon B.
AU - Kwiatkowski, David J.
AU - Creighton, Chad J.
N1 - Funding Information:
This work was supported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP120713 C2 (C.J.C.), and by NIH grants 5P50CA098258 (G.B.M.), 5U01CA168394 (G.B.M.), U24CA143883 (G.B.M.), 2P50CA101942-11A1 (D.J.K.), 1R21CA191687 (D.J.K.), 5P01CA120964 (D.J.K.), CA175486 (H.L.), CA209851 (H.L. and G.B.M.), P30CA125123 (C.J.C.), and Cancer Center Support Grant (CCSG) P30CA016672. G.B.M. has licensed an HRD assay to Myriad Genetics and is an SAB member/consultant with AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, Medimmune, Nuevolution, Pfizer, Precision Medicine, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, and Tarveda, and has stock options with Catena Pharmaceuticals, ImmunoMet, Spindle Top Ventures, and Tarveda. S.W. is a consultant with AstraZeneca, Clovis Oncology, Genentech, Medivation, Casdin Capital, and Vermillion. G.B.M. receives research support from Abbvie, Adelson Medical Research Foundation, AstraZeneca, the Breast Cancer Research Foundation, Critical Outcomes Technology, Horizon Diagnostics, Illumina, Ionis, Karus Therapeutics, Komen Research Foundation, Nanostring, Pfizer, Takeda/Millennium Pharmaceuticals, and Tesaro.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/6/12
Y1 - 2017/6/12
N2 - 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.
AB - 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.
KW - PI3K/AKT/mTOR pathway
KW - The Cancer Genome Atlas
KW - integrative genomics analysis
KW - pan-cancer analysis
KW - proteomics
KW - reverse-phase protein arrays
UR - http://www.scopus.com/inward/record.url?scp=85019369051&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019369051&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2017.04.013
DO - 10.1016/j.ccell.2017.04.013
M3 - Article
C2 - 28528867
AN - SCOPUS:85019369051
VL - 31
SP - 820-832.e3
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -