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

126 Scopus citations

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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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

A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. / Zhang, Yiqun; Kwok-Shing Ng, Patrick; Kucherlapati, Melanie; Chen, Fengju; Liu, Yuexin; Tsang, Yiu Huen; de Velasco, Guillermo; Jeong, Kang Jin; Akbani, Rehan; Hadjipanayis, Angela; Pantazi, Angeliki; Bristow, Christopher A.; Lee, Eunjung; Mahadeshwar, Harshad S.; Tang, Jiabin; Zhang, Jianhua; Yang, Lixing; Seth, Sahil; Lee, Semin; Ren, Xiaojia; Song, Xingzhi; Sun, Huandong; Seidman, Jonathan; Luquette, Lovelace J.; Xi, Ruibin; Chin, Lynda; Protopopov, Alexei; Westbrook, Thomas F.; Shelley, Carl Simon; Choueiri, Toni K.; Ittmann, Michael; Van Waes, Carter; Weinstein, John N.; Liang, Han; Henske, Elizabeth P.; Godwin, Andrew K.; Park, Peter J.; Kucherlapati, Raju; Scott, Kenneth L.; Mills, Gordon B.; Kwiatkowski, David J.; Creighton, Chad J.

In: Cancer Cell, Vol. 31, No. 6, 12.06.2017, p. 820-832.e3.

Research output: Contribution to journal › Article

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

Zhang, Yiqun ; Kwok-Shing Ng, Patrick ; Kucherlapati, Melanie ; Chen, Fengju ; Liu, Yuexin ; Tsang, Yiu Huen ; de Velasco, Guillermo ; Jeong, Kang Jin ; Akbani, Rehan ; Hadjipanayis, Angela ; Pantazi, Angeliki ; Bristow, Christopher A. ; Lee, Eunjung ; Mahadeshwar, Harshad S. ; Tang, Jiabin ; Zhang, Jianhua ; Yang, Lixing ; Seth, Sahil ; Lee, Semin ; Ren, Xiaojia ; Song, Xingzhi ; Sun, Huandong ; Seidman, Jonathan ; Luquette, Lovelace J. ; Xi, Ruibin ; Chin, Lynda ; Protopopov, Alexei ; Westbrook, Thomas F. ; Shelley, Carl Simon ; Choueiri, Toni K. ; Ittmann, Michael ; Van Waes, Carter ; Weinstein, John N. ; Liang, Han ; Henske, Elizabeth P. ; Godwin, Andrew K. ; Park, Peter J. ; Kucherlapati, Raju ; Scott, Kenneth L. ; Mills, Gordon B. ; Kwiatkowski, David J. ; Creighton, Chad J. / A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. In: Cancer Cell. 2017 ; Vol. 31, No. 6. pp. 820-832.e3.

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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.",

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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.

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AU - Yang, Lixing

AU - Seth, Sahil

AU - Lee, Semin

AU - Ren, Xiaojia

AU - Song, Xingzhi

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AU - Seidman, Jonathan

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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.

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