A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

The Cancer Genome Atlas Research Network

doi:10.1016/j.cell.2018.03.027

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

The Cancer Genome Atlas Research Network

School of Biomedical Sciences

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

205 Citations (Scopus)

Abstract

The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers. Causal enhancer-target-gene relationships are inferred from a systematic analysis of 33 cancer types.

Original language	English
Pages (from-to)	386-399.e12
Journal	Cell
Volume	173
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2018.03.027
Publication status	Published - 5 Apr 2018

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10.1016/j.cell.2018.03.027Licence: CC BY-NC-ND

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@article{da0c8c55b4d245729eaf1eb08e2e13a9,

title = "A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples",

abstract = "The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers. Causal enhancer-target-gene relationships are inferred from a systematic analysis of 33 cancer types.",

keywords = "aneuploidy, chromatin state, enhancer expression, mutation burden, pan-cancer analysis, PD-L1 expression, prognostic markers, The Cancer Genome Atlas",

author = "{The Cancer Genome Atlas Research Network} and Han Chen and Chunyan Li and Xinxin Peng and Zhicheng Zhou and Weinstein, {John N.} 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 Hailei Zhang and Brady Bernard and Nyasha Chambwe and Varsha Dhankani and Theo Knijnenburg and Roger Kramer and Kalle Leinonen and Yuexin Liu and Michael Miller and Sheila Reynolds and Ilya Shmulevich and Vesteinn Thorsson and Wei Zhang and Rehan Akbani and Broom, {Bradley M.} and Hegde, {Apurva M.} and Zhenlin Ju and Kanchi, {Rupa S.} and Anil Korkut and Jun Li and Han Liang and Shiyun Ling and Wenbin Liu and Yiling Lu and Mills, {Gordon B.} and Ng, {Kwok Shing} and Arvind Rao and Michael Ryan and Jing Wang and Weinstein, {John N.} and Jiexin Zhang and Adam Abeshouse and Joshua Armenia and Debyani Chakravarty and Chatila, {Walid K.} and {de Bruijn}, Ino and Jianjiong Gao and Gross, {Benjamin E.} and Heins, {Zachary J.} and Ritika Kundra and Konnor La and Marc Ladanyi and Augustin Luna and Nissan, {Moriah G.} and Angelica Ochoa and Phillips, {Sarah M.} and Ed Reznik and Francisco Sanchez-Vega and Chris Sander and Nikolaus Schultz and Robert Sheridan and Sumer, {S. Onur} and Yichao Sun and Taylor, {Barry S.} and Jioajiao Wang and Hongxin Zhang and Pavana Anur and Myron Peto and Paul Spellman and Christopher Benz and Stuart, {Joshua M.} and Wong, {Christopher K.} and Christina Yau and Hayes, {D. Neil} and Parker, {Joel S.} and Wilkerson, {Matthew D.} and Adrian Ally and Miruna Balasundaram and Reanne Bowlby and Denise Brooks and Rebecca Carlsen and Eric Chuah and Noreen Dhalla and Robert Holt and Jones, {Steven J.M.} and Katayoon Kasaian and Darlene Lee and Yussanne Ma and Marra, {Marco A.} and Michael Mayo and Moore, {Richard A.} and Mungall, {Andrew J.} and Karen Mungall and Robertson, {A. Gordon} and Sara Sadeghi and Schein, {Jacqueline E.} and Payal Sipahimalani and Angela Tam and Nina Thiessen and Kane Tse and Tina Wong and Berger, {Ashton C.} and Rameen Beroukhim and Cherniack, {Andrew D.} and Carrie Cibulskis and Gabriel, {Stacey B.} and Gao, {Galen F.} and Gavin Ha and Matthew Meyerson and Schumacher, {Steven E.} and Juliann Shih and Kucherlapati, {Melanie H.} and Kucherlapati, {Raju S.} and Stephen Baylin and Leslie Cope and Ludmila Danilova and Bootwalla, {Moiz S.} and Lai, {Phillip H.} and Maglinte, {Dennis T.} and {Van Den Berg}, {David J.} and Weisenberger, {Daniel J.} and Auman, {J. Todd} and Saianand Balu and Tom Bodenheimer and Cheng Fan and Hoadley, {Katherine A.} and Hoyle, {Alan P.} and Jefferys, {Stuart R.} and Jones, {Corbin D.} and Shaowu Meng and Mieczkowski, {Piotr A.} and Mose, {Lisle E.} and Perou, {Amy H.} and Perou, {Charles M.} and Jeffrey Roach and Yan Shi and Simons, {Janae V.} and Tara Skelly and Soloway, {Matthew G.} and Donghui Tan and Umadevi Veluvolu and Huihui Fan and Toshinori Hinoue and Laird, {Peter W.} and Hui Shen and Wanding Zhou and Michelle Bellair and Kyle Chang and Kyle Covington and Creighton, {Chad J.} and Huyen Dinh and Doddapaneni, {Harsha Vardhan} and Donehower, {Lawrence A.} and Jennifer Drummond and Gibbs, {Richard A.} and Robert Glenn and Walker Hale and Yi Han and Jianhong Hu and Viktoriya Korchina and Sandra Lee and Lora Lewis and Wei Li and Xiuping Liu and Margaret Morgan and Donna Morton and Donna Muzny and Jireh Santibanez and Margi Sheth and Eve Shinbrot and Linghua Wang and Min Wang and Wheeler, {David A.} and Liu Xi and Fengmei Zhao and Julian Hess and Appelbaum, {Elizabeth L.} and Matthew Bailey and Cordes, {Matthew G.} and Li Ding and Fronick, {Catrina C.} and Fulton, {Lucinda A.} and Fulton, {Robert S.} and Cyriac Kandoth and Mardis, {Elaine R.} and McLellan, {Michael D.} and Miller, {Christopher A.} and Schmidt, {Heather K.} and Wilson, {Richard K.} and Daniel Crain and Erin Curley and Johanna Gardner and Kevin Lau and David Mallery and Scott Morris and Joseph Paulauskis and Robert Penny and Candace Shelton and Troy Shelton and Mark Sherman and Eric Thompson and Peggy Yena and Jay Bowen and Gastier-Foster, {Julie M.} and Mark Gerken and Leraas, {Kristen M.} and Lichtenberg, {Tara M.} and Ramirez, {Nilsa C.} and Lisa Wise and Erik Zmuda and Niall Corcoran and Tony Costello and Christopher Hovens and Carvalho, {Andre L.} and {de Carvalho}, {Ana C.} and Fregnani, {Jos{\'e} H.} and Adhemar Longatto-Filho and Reis, {Rui M.} and Cristovam Scapulatempo-Neto and Silveira, {Henrique C.S.} and Vidal, {Daniel O.} and Jenette Creaney",

year = "2018",

month = apr,

day = "5",

doi = "10.1016/j.cell.2018.03.027",

language = "English",

volume = "173",

pages = "386--399.e12",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

AU - The Cancer Genome Atlas Research Network

AU - Chen, Han

AU - Li, Chunyan

AU - Peng, Xinxin

AU - Zhou, Zhicheng

AU - Weinstein, John N.

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 - Zhang, Hailei

AU - Bernard, Brady

AU - Chambwe, Nyasha

AU - Dhankani, Varsha

AU - Knijnenburg, Theo

AU - Kramer, Roger

AU - Leinonen, Kalle

AU - Liu, Yuexin

AU - Miller, Michael

AU - Reynolds, Sheila

AU - Shmulevich, Ilya

AU - Thorsson, Vesteinn

AU - Zhang, Wei

AU - Akbani, Rehan

AU - Broom, Bradley M.

AU - Hegde, Apurva M.

AU - Ju, Zhenlin

AU - Kanchi, Rupa S.

AU - Korkut, Anil

AU - Li, Jun

AU - Liang, Han

AU - Ling, Shiyun

AU - Liu, Wenbin

AU - Lu, Yiling

AU - Mills, Gordon B.

AU - Ng, Kwok Shing

AU - Rao, Arvind

AU - Ryan, Michael

AU - Wang, Jing

AU - Weinstein, John N.

AU - Zhang, Jiexin

AU - Abeshouse, Adam

AU - Armenia, Joshua

AU - Chakravarty, Debyani

AU - Chatila, Walid K.

AU - de Bruijn, Ino

AU - Gao, Jianjiong

AU - Gross, Benjamin E.

AU - Heins, Zachary J.

AU - Kundra, Ritika

AU - La, Konnor

AU - Ladanyi, Marc

AU - Luna, Augustin

AU - Nissan, Moriah G.

AU - Ochoa, Angelica

AU - Phillips, Sarah M.

AU - Reznik, Ed

AU - Sanchez-Vega, Francisco

AU - Sander, Chris

AU - Schultz, Nikolaus

AU - Sheridan, Robert

AU - Sumer, S. Onur

AU - Sun, Yichao

AU - Taylor, Barry S.

AU - Wang, Jioajiao

AU - Zhang, Hongxin

AU - Anur, Pavana

AU - Peto, Myron

AU - Spellman, Paul

AU - Benz, Christopher

AU - Stuart, Joshua M.

AU - Wong, Christopher K.

AU - Yau, Christina

AU - Hayes, D. Neil

AU - Parker, Joel S.

AU - Wilkerson, Matthew D.

AU - Ally, Adrian

AU - Balasundaram, Miruna

AU - Bowlby, Reanne

AU - Brooks, Denise

AU - Carlsen, Rebecca

AU - Chuah, Eric

AU - Dhalla, Noreen

AU - Holt, Robert

AU - Jones, Steven J.M.

AU - Kasaian, Katayoon

AU - Lee, Darlene

AU - Ma, Yussanne

AU - Marra, Marco A.

AU - Mayo, Michael

AU - Moore, Richard A.

AU - Mungall, Andrew J.

AU - Mungall, Karen

AU - Robertson, A. Gordon

AU - Sadeghi, Sara

AU - Schein, Jacqueline E.

AU - Sipahimalani, Payal

AU - Tam, Angela

AU - Thiessen, Nina

AU - Tse, Kane

AU - Wong, Tina

AU - Berger, Ashton C.

AU - Beroukhim, Rameen

AU - Cherniack, Andrew D.

AU - Cibulskis, Carrie

AU - Gabriel, Stacey B.

AU - Gao, Galen F.

AU - Ha, Gavin

AU - Meyerson, Matthew

AU - Schumacher, Steven E.

AU - Shih, Juliann

AU - Kucherlapati, Melanie H.

AU - Kucherlapati, Raju S.

AU - Baylin, Stephen

AU - Cope, Leslie

AU - Danilova, Ludmila

AU - Bootwalla, Moiz S.

AU - Lai, Phillip H.

AU - Maglinte, Dennis T.

AU - Van Den Berg, David J.

AU - Weisenberger, Daniel J.

AU - Auman, J. Todd

AU - Balu, Saianand

AU - Bodenheimer, Tom

AU - Fan, Cheng

AU - Hoadley, Katherine A.

AU - Hoyle, Alan P.

AU - Jefferys, Stuart R.

AU - Jones, Corbin D.

AU - Meng, Shaowu

AU - Mieczkowski, Piotr A.

AU - Mose, Lisle E.

AU - Perou, Amy H.

AU - Perou, Charles M.

AU - Roach, Jeffrey

AU - Shi, Yan

AU - Simons, Janae V.

AU - Skelly, Tara

AU - Soloway, Matthew G.

AU - Tan, Donghui

AU - Veluvolu, Umadevi

AU - Fan, Huihui

AU - Hinoue, Toshinori

AU - Laird, Peter W.

AU - Shen, Hui

AU - Zhou, Wanding

AU - Bellair, Michelle

AU - Chang, Kyle

AU - Covington, Kyle

AU - Creighton, Chad J.

AU - Dinh, Huyen

AU - Doddapaneni, Harsha Vardhan

AU - Donehower, Lawrence A.

AU - Drummond, Jennifer

AU - Gibbs, Richard A.

AU - Glenn, Robert

AU - Hale, Walker

AU - Han, Yi

AU - Hu, Jianhong

AU - Korchina, Viktoriya

AU - Lee, Sandra

AU - Lewis, Lora

AU - Li, Wei

AU - Liu, Xiuping

AU - Morgan, Margaret

AU - Morton, Donna

AU - Muzny, Donna

AU - Santibanez, Jireh

AU - Sheth, Margi

AU - Shinbrot, Eve

AU - Wang, Linghua

AU - Wang, Min

AU - Wheeler, David A.

AU - Xi, Liu

AU - Zhao, Fengmei

AU - Hess, Julian

AU - Appelbaum, Elizabeth L.

AU - Bailey, Matthew

AU - Cordes, Matthew G.

AU - Ding, Li

AU - Fronick, Catrina C.

AU - Fulton, Lucinda A.

AU - Fulton, Robert S.

AU - Kandoth, Cyriac

AU - Mardis, Elaine R.

AU - McLellan, Michael D.

AU - Miller, Christopher A.

AU - Schmidt, Heather K.

AU - Wilson, Richard K.

AU - Crain, Daniel

AU - Curley, Erin

AU - Gardner, Johanna

AU - Lau, Kevin

AU - Mallery, David

AU - Morris, Scott

AU - Paulauskis, Joseph

AU - Penny, Robert

AU - Shelton, Candace

AU - Shelton, Troy

AU - Sherman, Mark

AU - Thompson, Eric

AU - Yena, Peggy

AU - Bowen, Jay

AU - Gastier-Foster, Julie M.

AU - Gerken, Mark

AU - Leraas, Kristen M.

AU - Lichtenberg, Tara M.

AU - Ramirez, Nilsa C.

AU - Wise, Lisa

AU - Zmuda, Erik

AU - Corcoran, Niall

AU - Costello, Tony

AU - Hovens, Christopher

AU - Carvalho, Andre L.

AU - de Carvalho, Ana C.

AU - Fregnani, José H.

AU - Longatto-Filho, Adhemar

AU - Reis, Rui M.

AU - Scapulatempo-Neto, Cristovam

AU - Silveira, Henrique C.S.

AU - Vidal, Daniel O.

AU - Creaney, Jenette

PY - 2018/4/5

Y1 - 2018/4/5

N2 - The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers. Causal enhancer-target-gene relationships are inferred from a systematic analysis of 33 cancer types.

AB - The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers. Causal enhancer-target-gene relationships are inferred from a systematic analysis of 33 cancer types.

KW - aneuploidy

KW - chromatin state

KW - enhancer expression

KW - mutation burden

KW - pan-cancer analysis

KW - PD-L1 expression

KW - prognostic markers

KW - The Cancer Genome Atlas

UR - http://www.scopus.com/inward/record.url?scp=85044921094&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.03.027

DO - 10.1016/j.cell.2018.03.027

M3 - Article

AN - SCOPUS:85044921094

SN - 0092-8674

VL - 173

SP - 386-399.e12

JO - Cell

JF - Cell

IS - 2

ER -

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

Abstract

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