Comprehensive Characterization of Cancer Driver Genes and Mutations

The MC3 Working Group; The Cancer Genome Atlas Research Network

doi:10.1016/j.cell.2018.02.060

Comprehensive Characterization of Cancer Driver Genes and Mutations

The MC3 Working Group, The Cancer Genome Atlas Research Network

School of Biomedical Sciences

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

808 Citations (Web of Science)

Abstract

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%–85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors. A comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples.

Original language	English
Pages (from-to)	371-385.e18
Journal	Cell
Volume	173
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2018.02.060
Publication status	Published - 5 Apr 2018

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10.1016/j.cell.2018.02.060Licence: CC BY-NC-ND

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@article{c65af413cdc5428bbd4fefd2baadba6b,

title = "Comprehensive Characterization of Cancer Driver Genes and Mutations",

abstract = "Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%–85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors. A comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples.",

keywords = "driver gene discovery, mutations of clinical relevance, oncology, structure analysis",

author = "{The MC3 Working Group} and {The Cancer Genome Atlas Research Network} and Bailey, {Matthew H.} and Collin Tokheim and Eduard Porta-Pardo and Sohini Sengupta and Denis Bertrand and Amila Weerasinghe and Antonio Colaprico and Wendl, {Michael C.} and Jaegil Kim and Brendan Reardon and Ng, {Patrick Kwok Shing} and Jeong, {Kang Jin} and Song Cao and Zixing Wang and Jianjiong Gao and Qingsong Gao and Fang Wang and Liu, {Eric Minwei} and Loris Mularoni and Carlota Rubio-Perez and Niranjan Nagarajan and Isidro Cort{\'e}s-Ciriano and Zhou, {Daniel Cui} and Liang, {Wen Wei} and Hess, {Julian M.} and Yellapantula, {Venkata D.} and David Tamborero and Abel Gonzalez-Perez and Chayaporn Suphavilai and Ko, {Jia Yu} and Ekta Khurana and Park, {Peter J.} and {Van Allen}, {Eliezer M.} and Han Liang 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 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 Lawrence, {Michael S.} and Pei Lin and Sam Meier and Noble, {Michael S.} and Gordon Saksena and Doug Voet and Hongxin 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 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 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 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 Jenette Creaney",

year = "2018",

month = apr,

day = "5",

doi = "10.1016/j.cell.2018.02.060",

language = "English",

volume = "173",

pages = "371--385.e18",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Comprehensive Characterization of Cancer Driver Genes and Mutations

AU - The MC3 Working Group

AU - The Cancer Genome Atlas Research Network

AU - Bailey, Matthew H.

AU - Tokheim, Collin

AU - Porta-Pardo, Eduard

AU - Sengupta, Sohini

AU - Bertrand, Denis

AU - Weerasinghe, Amila

AU - Colaprico, Antonio

AU - Wendl, Michael C.

AU - Kim, Jaegil

AU - Reardon, Brendan

AU - Ng, Patrick Kwok Shing

AU - Jeong, Kang Jin

AU - Cao, Song

AU - Wang, Zixing

AU - Gao, Jianjiong

AU - Gao, Qingsong

AU - Wang, Fang

AU - Liu, Eric Minwei

AU - Mularoni, Loris

AU - Rubio-Perez, Carlota

AU - Nagarajan, Niranjan

AU - Cortés-Ciriano, Isidro

AU - Zhou, Daniel Cui

AU - Liang, Wen Wei

AU - Hess, Julian M.

AU - Yellapantula, Venkata D.

AU - Tamborero, David

AU - Gonzalez-Perez, Abel

AU - Suphavilai, Chayaporn

AU - Ko, Jia Yu

AU - Khurana, Ekta

AU - Park, Peter J.

AU - Van Allen, Eliezer M.

AU - Liang, Han

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 - 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 - Lawrence, Michael S.

AU - Lin, Pei

AU - Meier, Sam

AU - Noble, Michael S.

AU - Saksena, Gordon

AU - Voet, Doug

AU - Zhang, Hongxin

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 - 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 - 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 - 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 - Creaney, Jenette

PY - 2018/4/5

Y1 - 2018/4/5

N2 - Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%–85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors. A comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples.

AB - Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%–85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors. A comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples.

KW - driver gene discovery

KW - mutations of clinical relevance

KW - oncology

KW - structure analysis

UR - http://www.scopus.com/inward/record.url?scp=85044623848&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.02.060

DO - 10.1016/j.cell.2018.02.060

M3 - Article

C2 - 29625053

AN - SCOPUS:85044623848

VL - 173

SP - 371-385.e18

JO - Cell

JF - Cell

SN - 0092-8674

IS - 2

ER -

Comprehensive Characterization of Cancer Driver Genes and Mutations

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