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

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 RenXingzhi 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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	820-832.e3
Journal	Cancer Cell
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2017.04.013
State	Published - Jun 12 2017
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccell.2017.04.013

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Zhang, Y., Kwok-Shing Ng, P., Kucherlapati, M., Chen, F., Liu, Y., Tsang, Y. H., de Velasco, G., Jeong, K. J., Akbani, R., Hadjipanayis, A., Pantazi, A., Bristow, C. A., Lee, E., Mahadeshwar, H. S., Tang, J., Zhang, J., Yang, L., Seth, S., Lee, S., ... Creighton, C. J. (2017). A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell, 31(6), 820-832.e3. https://doi.org/10.1016/j.ccell.2017.04.013

Zhang, Y, Kwok-Shing Ng, P, Kucherlapati, M, Chen, F, Liu, Y, Tsang, YH, de Velasco, G, Jeong, KJ, Akbani, R, Hadjipanayis, A, Pantazi, A, Bristow, CA, Lee, E, Mahadeshwar, HS, Tang, J, Zhang, J, Yang, L, Seth, S, Lee, S, Ren, X, Song, X, Sun, H, Seidman, J, Luquette, LJ, Xi, R, Chin, L, Protopopov, A, Westbrook, TF, Shelley, CS, Choueiri, TK, Ittmann, M, Van Waes, C, Weinstein, JN, Liang, H, Henske, EP, Godwin, AK, Park, PJ, Kucherlapati, R, Scott, KL, Mills, GB, Kwiatkowski, DJ & Creighton, CJ 2017, 'A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations', Cancer Cell, vol. 31, no. 6, pp. 820-832.e3. https://doi.org/10.1016/j.ccell.2017.04.013

@article{46ec6307252c4fcda354d160165e18c9,

title = "A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations",

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",

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

note = "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: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = jun,

day = "12",

doi = "10.1016/j.ccell.2017.04.013",

language = "English (US)",

volume = "31",

pages = "820--832.e3",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

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

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UR - http://www.scopus.com/inward/citedby.url?scp=85019369051&partnerID=8YFLogxK

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DO - 10.1016/j.ccell.2017.04.013

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AN - SCOPUS:85019369051

VL - 31

SP - 820-832.e3

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 6

ER -

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

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Keywords

ASJC Scopus subject areas

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