Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Franz X. Schaub; Varsha Dhankani; Ashton C. Berger; Mihir Trivedi; Anne B. Richardson; Reid Shaw; Wei Zhao; Xiaoyang Zhang; Andrea Ventura; Yuexin Liu; Donald E. Ayer; Peter J. Hurlin; Andrew D. Cherniack; Robert N. Eisenman; Brady Bernard; Carla Grandori; Samantha J. Caesar-Johnson; John A. Demchok; Ina Felau; Melpomeni Kasapi; Martin L. Ferguson; Carolyn M. Hutter; Heidi J. Sofia; Roy Tarnuzzer; Zhining Wang; Liming Yang; Jean C. Zenklusen; Jiashan (Julia) Zhang; Sudha Chudamani; Jia Liu; Laxmi Lolla; Rashi Naresh; Todd Pihl; Qiang Sun; Yunhu Wan; Ye Wu; Juok Cho; Timothy DeFreitas; Scott Frazer; Nils Gehlenborg; Gad Getz; David I. Heiman; Jaegil Kim; Michael S. Lawrence; Pei Lin; Sam Meier; Michael S. Noble; Gordon Saksena; Doug Voet; Ronald de Krijger

doi:10.1016/j.cels.2018.03.003

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Franz X. Schaub, Varsha Dhankani, Ashton C. Berger, Mihir Trivedi, Anne B. Richardson, Reid Shaw, Wei Zhao, Xiaoyang Zhang, Andrea Ventura, Yuexin Liu, Donald E. Ayer, Peter J. Hurlin, Andrew D. Cherniack, Robert N. Eisenman, Brady Bernard, Carla Grandori, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni KasapiMartin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Ronald de Krijger,

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

Abstract

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics.

Original language	English
Pages (from-to)	282-300.e2
Journal	Cell Systems
Volume	6
Issue number	3
DOIs	https://doi.org/10.1016/j.cels.2018.03.003
Publication status	Published - 28 Mar 2018

Keywords

MAX
MNT
MYC genomic alterations
TCGA
The Cancer Genome Atlas

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10.1016/j.cels.2018.03.003

schaubFinal published version, 6.45 MBLicence: CC BY

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Schaub, F. X., Dhankani, V., Berger, A. C., Trivedi, M., Richardson, A. B., Shaw, R., Zhao, W., Zhang, X., Ventura, A., Liu, Y., Ayer, D. E., Hurlin, P. J., Cherniack, A. D., Eisenman, R. N., Bernard, B., Grandori, C., Caesar-Johnson, S. J., Demchok, J. A., Felau, I. (2018). Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas. Cell Systems, 6(3), 282-300.e2. https://doi.org/10.1016/j.cels.2018.03.003

@article{5f3d022366d14d23a1a26dd1ffe12369,

title = "Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas",

abstract = "Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics.",

keywords = "MAX, MNT, MYC genomic alterations, TCGA, The Cancer Genome Atlas",

author = "Schaub, {Franz X.} and Varsha Dhankani and Berger, {Ashton C.} and Mihir Trivedi and Richardson, {Anne B.} and Reid Shaw and Wei Zhao and Xiaoyang Zhang and Andrea Ventura and Yuexin Liu and Ayer, {Donald E.} and Hurlin, {Peter J.} and Cherniack, {Andrew D.} and Eisenman, {Robert N.} and Brady Bernard and Carla Grandori and Caesar-Johnson, {Samantha J.} and Demchok, {John A.} and Ina Felau and Melpomeni Kasapi and Ferguson, {Martin L.} and Hutter, {Carolyn M.} and Sofia, {Heidi J.} and Roy Tarnuzzer and Zhining Wang and Liming Yang and Zenklusen, {Jean C.} and Zhang, {Jiashan (Julia)} and Sudha Chudamani and Jia Liu and Laxmi Lolla and Rashi Naresh and Todd Pihl and Qiang Sun and Yunhu Wan and Ye Wu and Juok Cho and Timothy DeFreitas and Scott Frazer and Nils Gehlenborg and Gad Getz and Heiman, {David I.} and Jaegil Kim and Lawrence, {Michael S.} and Pei Lin and Sam Meier and Noble, {Michael S.} and Gordon Saksena and Doug Voet and {de Krijger}, Ronald",

note = "Funding Information: Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine. 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. 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. Kyle R. Covington is an employee of Castle Biosciences. 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. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine. 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. 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. Bin Feng is an employee and shareholder of TESARO. 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. 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. and a shareholder and advisory board member of Tempus. 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. Funding Information: The MYC team would like to acknowledge Dr. Theo Knijnenburg for guidance and discussions regarding the statistical analysis and interpretation conducted as part of this research. We would also like to thank Dr. Bruno Amati, Dr. Christopher Kemp, and Dr. Goldie Lui for helpful input on the manuscript. This work was supported in part with grants from NIH ( 4U01CA176303-04 to C.G., U24CA143867 to A.C.B. and A.D.C., RO1CA57138 to R.N.E., and 5R01CA149707 to A.V.) and research funding from SEngine Precision Medicine and Cure First to C.G., F.X.S., V.D., and R.S. P.J.H. is supported by grants from Shriners Hospitals for Children and Leukemia and Lymphoma Society . Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = mar,

day = "28",

doi = "10.1016/j.cels.2018.03.003",

language = "English",

volume = "6",

pages = "282--300.e2",

number = "3",

}

Schaub, FX, Dhankani, V, Berger, AC, Trivedi, M, Richardson, AB, Shaw, R, Zhao, W, Zhang, X, Ventura, A, Liu, Y, Ayer, DE, Hurlin, PJ, Cherniack, AD, Eisenman, RN, Bernard, B, Grandori, C, Caesar-Johnson, SJ, Demchok, JA, Felau, I, Kasapi, M, Ferguson, ML, Hutter, CM, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zenklusen, JC, Zhang, J, Chudamani, S, Liu, J, Lolla, L, Naresh, R, Pihl, T, Sun, Q, Wan, Y, Wu, Y, Cho, J, DeFreitas, T, Frazer, S, Gehlenborg, N, Getz, G, Heiman, DI, Kim, J, Lawrence, MS, Lin, P, Meier, S, Noble, MS, Saksena, G, Voet, D, de Krijger, R 2018, 'Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas', Cell Systems, vol. 6, no. 3, pp. 282-300.e2. https://doi.org/10.1016/j.cels.2018.03.003

TY - JOUR

T1 - Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

AU - Schaub, Franz X.

AU - Dhankani, Varsha

AU - Berger, Ashton C.

AU - Trivedi, Mihir

AU - Richardson, Anne B.

AU - Shaw, Reid

AU - Zhao, Wei

AU - Zhang, Xiaoyang

AU - Ventura, Andrea

AU - Liu, Yuexin

AU - Ayer, Donald E.

AU - Hurlin, Peter J.

AU - Cherniack, Andrew D.

AU - Eisenman, Robert N.

AU - Bernard, Brady

AU - Grandori, Carla

AU - Caesar-Johnson, Samantha J.

AU - Demchok, John A.

AU - Felau, Ina

AU - Kasapi, Melpomeni

AU - Ferguson, Martin L.

AU - Hutter, Carolyn M.

AU - Sofia, Heidi J.

AU - Tarnuzzer, Roy

AU - Wang, Zhining

AU - Yang, Liming

AU - Zenklusen, Jean C.

AU - Zhang, Jiashan (Julia)

AU - Chudamani, Sudha

AU - Liu, Jia

AU - Lolla, Laxmi

AU - Naresh, Rashi

AU - Pihl, Todd

AU - Sun, Qiang

AU - Wan, Yunhu

AU - Wu, Ye

AU - Cho, Juok

AU - DeFreitas, Timothy

AU - Frazer, Scott

AU - Gehlenborg, Nils

AU - Getz, Gad

AU - Heiman, David I.

AU - Kim, Jaegil

AU - Lawrence, Michael S.

AU - Lin, Pei

AU - Meier, Sam

AU - Noble, Michael S.

AU - Saksena, Gordon

AU - Voet, Doug

AU - de Krijger, Ronald

N1 - Funding Information: Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine. 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. 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. Kyle R. Covington is an employee of Castle Biosciences. 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. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine. 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. 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. Bin Feng is an employee and shareholder of TESARO. 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. 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. and a shareholder and advisory board member of Tempus. 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. Funding Information: The MYC team would like to acknowledge Dr. Theo Knijnenburg for guidance and discussions regarding the statistical analysis and interpretation conducted as part of this research. We would also like to thank Dr. Bruno Amati, Dr. Christopher Kemp, and Dr. Goldie Lui for helpful input on the manuscript. This work was supported in part with grants from NIH ( 4U01CA176303-04 to C.G., U24CA143867 to A.C.B. and A.D.C., RO1CA57138 to R.N.E., and 5R01CA149707 to A.V.) and research funding from SEngine Precision Medicine and Cure First to C.G., F.X.S., V.D., and R.S. P.J.H. is supported by grants from Shriners Hospitals for Children and Leukemia and Lymphoma Society . Publisher Copyright: © 2018 The Authors

PY - 2018/3/28

Y1 - 2018/3/28

N2 - Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics.

AB - Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics.

KW - MAX

KW - MNT

KW - MYC genomic alterations

KW - TCGA

KW - The Cancer Genome Atlas

UR - http://www.scopus.com/inward/record.url?scp=85044336302&partnerID=8YFLogxK

U2 - 10.1016/j.cels.2018.03.003

DO - 10.1016/j.cels.2018.03.003

M3 - Article

AN - SCOPUS:85044336302

SN - 2405-4712

VL - 6

SP - 282-300.e2

JO - Cell Systems

JF - Cell Systems

IS - 3

ER -

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

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Keywords

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