Oncogenic Signaling Pathways in The Cancer Genome Atlas

Francisco Sanchez-Vega; Marco Mina; Joshua Armenia; Walid K. Chatila; Augustin Luna; Konnor C. La; Sofia Dimitriadoy; David L. Liu; Havish S. Kantheti; Sadegh Saghafinia; Debyani Chakravarty; Foysal Daian; Qingsong Gao; Matthew H. Bailey; Wen Wei Liang; Steven M. Foltz; Ilya Shmulevich; Li Ding; Zachary J. Heins; Angelica Ochoa; Benjamin E. Gross; Jianjiong Gao; Hongxin Zhang; Ritika Kundra; Cyriac Kandoth; Istemi Bahceci; Leonard Dervishi; Ugur Dogrusoz; Wanding Zhou; Hui Shen; Peter W. Laird; Gregory P. Way; Casey S. Greene; Han Liang; Yonghong Xiao; Chen Wang; Antonio Iavarone; Alice H. Berger; Trever G. Bivona; Alexander J. Lazar; Gary D. Hammer; Thomas Giordano; Lawrence N. Kwong; Grant McArthur; Chenfei Huang; Aaron D. Tward; Mitchell J. Frederick; Frank McCormick; Jiashan (Julia) Zhang; Ronald de Krijger

doi:10.1016/j.cell.2018.03.035

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Francisco Sanchez-Vega, Marco Mina, Joshua Armenia, Walid K. Chatila, Augustin Luna, Konnor C. La, Sofia Dimitriadoy, David L. Liu, Havish S. Kantheti, Sadegh Saghafinia, Debyani Chakravarty, Foysal Daian, Qingsong Gao, Matthew H. Bailey, Wen Wei Liang, Steven M. Foltz, Ilya Shmulevich, Li Ding, Zachary J. Heins, Angelica OchoaBenjamin E. Gross, Jianjiong Gao, Hongxin Zhang, Ritika Kundra, Cyriac Kandoth, Istemi Bahceci, Leonard Dervishi, Ugur Dogrusoz, Wanding Zhou, Hui Shen, Peter W. Laird, Gregory P. Way, Casey S. Greene, Han Liang, Yonghong Xiao, Chen Wang, Antonio Iavarone, Alice H. Berger, Trever G. Bivona, Alexander J. Lazar, Gary D. Hammer, Thomas Giordano, Lawrence N. Kwong, Grant McArthur, Chenfei Huang, Aaron D. Tward, Mitchell J. Frederick, Frank McCormick, Jiashan (Julia) Zhang, Ronald de Krijger,

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

1 Citation (Scopus)

Abstract

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.

Original language	English
Pages (from-to)	321-337.e10
Journal	Cell
Volume	173
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2018.03.035
Publication status	Published - 5 Apr 2018

Keywords

cancer genome atlas
cancer genomics
combination therapy
pan-cancer
PanCanAtlas
precision oncology
signaling pathways
TCGA
therapeutics
whole exome sequencing

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10.1016/j.cell.2018.03.035

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Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., Chakravarty, D., Daian, F., Gao, Q., Bailey, M. H., Liang, W. W., Foltz, S. M., Shmulevich, I., Ding, L., Heins, Z. J. (2018). Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell, 173(2), 321-337.e10. https://doi.org/10.1016/j.cell.2018.03.035

@article{65653b56a07345c68a69f0d3f3cd8268,

title = "Oncogenic Signaling Pathways in The Cancer Genome Atlas",

abstract = "Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.",

keywords = "cancer genome atlas, cancer genomics, combination therapy, pan-cancer, PanCanAtlas, precision oncology, signaling pathways, TCGA, therapeutics, whole exome sequencing",

author = "Francisco Sanchez-Vega and Marco Mina and Joshua Armenia and Chatila, {Walid K.} and Augustin Luna and La, {Konnor C.} and Sofia Dimitriadoy and Liu, {David L.} and Kantheti, {Havish S.} and Sadegh Saghafinia and Debyani Chakravarty and Foysal Daian and Qingsong Gao and Bailey, {Matthew H.} and Liang, {Wen Wei} and Foltz, {Steven M.} and Ilya Shmulevich and Li Ding and Heins, {Zachary J.} and Angelica Ochoa and Gross, {Benjamin E.} and Jianjiong Gao and Hongxin Zhang and Ritika Kundra and Cyriac Kandoth and Istemi Bahceci and Leonard Dervishi and Ugur Dogrusoz and Wanding Zhou and Hui Shen and Laird, {Peter W.} and Way, {Gregory P.} and Greene, {Casey S.} and Han Liang and Yonghong Xiao and Chen Wang and Antonio Iavarone and Berger, {Alice H.} and Bivona, {Trever G.} and Lazar, {Alexander J.} and Hammer, {Gary D.} and Thomas Giordano and Kwong, {Lawrence N.} and Grant McArthur and Chenfei Huang and Tward, {Aaron D.} and Frederick, {Mitchell J.} and Frank McCormick and Zhang, {Jiashan (Julia)} and {de Krijger}, Ronald",

note = "Funding Information: This work was supported by NIH Grants U54 HG003273 , U54 HG003067 , U54 HG003079 , U24 CA143799 , U24 CA143835 , U24 CA143840 , U24 CA143843 , U24 CA143845 , U24 CA143848 , U24 CA143858 , U24 CA143866 , U24 CA143867 , U24 CA143882 , U24 CA143883 , U24 CA144025 , P30 CA016672 . Funding Information: Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae. Publisher Copyright: {\textcopyright} 2018 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2018",

month = apr,

day = "5",

doi = "10.1016/j.cell.2018.03.035",

language = "English",

volume = "173",

pages = "321--337.e10",

number = "2",

}

Sanchez-Vega, F, Mina, M, Armenia, J, Chatila, WK, Luna, A, La, KC, Dimitriadoy, S, Liu, DL, Kantheti, HS, Saghafinia, S, Chakravarty, D, Daian, F, Gao, Q, Bailey, MH, Liang, WW, Foltz, SM, Shmulevich, I, Ding, L, Heins, ZJ, Ochoa, A, Gross, BE, Gao, J, Zhang, H, Kundra, R, Kandoth, C, Bahceci, I, Dervishi, L, Dogrusoz, U, Zhou, W, Shen, H, Laird, PW, Way, GP, Greene, CS, Liang, H, Xiao, Y, Wang, C, Iavarone, A, Berger, AH, Bivona, TG, Lazar, AJ, Hammer, GD, Giordano, T, Kwong, LN, McArthur, G, Huang, C, Tward, AD, Frederick, MJ, McCormick, F, Zhang, J, de Krijger, R 2018, 'Oncogenic Signaling Pathways in The Cancer Genome Atlas', Cell, vol. 173, no. 2, pp. 321-337.e10. https://doi.org/10.1016/j.cell.2018.03.035

TY - JOUR

T1 - Oncogenic Signaling Pathways in The Cancer Genome Atlas

AU - Sanchez-Vega, Francisco

AU - Mina, Marco

AU - Armenia, Joshua

AU - Chatila, Walid K.

AU - Luna, Augustin

AU - La, Konnor C.

AU - Dimitriadoy, Sofia

AU - Liu, David L.

AU - Kantheti, Havish S.

AU - Saghafinia, Sadegh

AU - Chakravarty, Debyani

AU - Daian, Foysal

AU - Gao, Qingsong

AU - Bailey, Matthew H.

AU - Liang, Wen Wei

AU - Foltz, Steven M.

AU - Shmulevich, Ilya

AU - Ding, Li

AU - Heins, Zachary J.

AU - Ochoa, Angelica

AU - Gross, Benjamin E.

AU - Gao, Jianjiong

AU - Zhang, Hongxin

AU - Kundra, Ritika

AU - Kandoth, Cyriac

AU - Bahceci, Istemi

AU - Dervishi, Leonard

AU - Dogrusoz, Ugur

AU - Zhou, Wanding

AU - Shen, Hui

AU - Laird, Peter W.

AU - Way, Gregory P.

AU - Greene, Casey S.

AU - Liang, Han

AU - Xiao, Yonghong

AU - Wang, Chen

AU - Iavarone, Antonio

AU - Berger, Alice H.

AU - Bivona, Trever G.

AU - Lazar, Alexander J.

AU - Hammer, Gary D.

AU - Giordano, Thomas

AU - Kwong, Lawrence N.

AU - McArthur, Grant

AU - Huang, Chenfei

AU - Tward, Aaron D.

AU - Frederick, Mitchell J.

AU - McCormick, Frank

AU - Zhang, Jiashan (Julia)

AU - de Krijger, Ronald

N1 - Funding Information: This work was supported by NIH Grants U54 HG003273 , U54 HG003067 , U54 HG003079 , U24 CA143799 , U24 CA143835 , U24 CA143840 , U24 CA143843 , U24 CA143845 , U24 CA143848 , U24 CA143858 , U24 CA143866 , U24 CA143867 , U24 CA143882 , U24 CA143883 , U24 CA144025 , P30 CA016672 . Funding Information: Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae. Publisher Copyright: © 2018 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2018/4/5

Y1 - 2018/4/5

N2 - Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.

AB - Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.

KW - cancer genome atlas

KW - cancer genomics

KW - combination therapy

KW - pan-cancer

KW - PanCanAtlas

KW - precision oncology

KW - signaling pathways

KW - TCGA

KW - therapeutics

KW - whole exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85044966521&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.03.035

DO - 10.1016/j.cell.2018.03.035

M3 - Article

AN - SCOPUS:85044966521

SN - 0092-8674

VL - 173

SP - 321-337.e10

JO - Cell

JF - Cell

IS - 2

ER -

Oncogenic Signaling Pathways in The Cancer Genome Atlas

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