Back to Search Start Over

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

Authors :
Theo A. Knijnenburg
Linghua Wang
Michael T. Zimmermann
Nyasha Chambwe
Galen F. Gao
Andrew D. Cherniack
Huihui Fan
Hui Shen
Gregory P. Way
Casey S. Greene
Yuexin Liu
Rehan Akbani
Bin Feng
Lawrence A. Donehower
Chase Miller
Yang Shen
Mostafa Karimi
Haoran Chen
Pora Kim
Peilin Jia
Eve Shinbrot
Shaojun Zhang
Jianfang Liu
Hai Hu
Matthew H. Bailey
Christina Yau
Denise Wolf
Zhongming Zhao
John N. Weinstein
Lei Li
Li Ding
Gordon B. Mills
Peter W. Laird
David A. Wheeler
Ilya Shmulevich
Raymond J. Monnat, Jr.
Yonghong Xiao
Chen Wang
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
Hailei Zhang
Brady Bernard
Varsha Dhankani
Theo Knijnenburg
Roger Kramer
Kalle Leinonen
Michael Miller
Sheila Reynolds
Vesteinn Thorsson
Wei Zhang
Bradley M. Broom
Apurva M. Hegde
Zhenlin Ju
Rupa S. Kanchi
Anil Korkut
Jun Li
Han Liang
Shiyun Ling
Wenbin Liu
Yiling Lu
Kwok-Shing Ng
Arvind Rao
Michael Ryan
Jing Wang
Jiexin Zhang
Adam Abeshouse
Joshua Armenia
Debyani Chakravarty
Walid K. Chatila
Ino de Bruijn
Jianjiong Gao
Benjamin E. Gross
Zachary J. Heins
Ritika Kundra
Konnor La
Marc Ladanyi
Augustin Luna
Moriah G. Nissan
Angelica Ochoa
Sarah M. Phillips
Ed Reznik
Francisco Sanchez-Vega
Chris Sander
Nikolaus Schultz
Robert Sheridan
S. Onur Sumer
Yichao Sun
Barry S. Taylor
Jioajiao Wang
Hongxin Zhang
Pavana Anur
Myron Peto
Paul Spellman
Christopher Benz
Joshua M. Stuart
Christopher K. Wong
D. Neil Hayes
Joel S. Parker
Matthew D. Wilkerson
Adrian Ally
Miruna Balasundaram
Reanne Bowlby
Denise Brooks
Rebecca Carlsen
Eric Chuah
Noreen Dhalla
Robert Holt
Steven J.M. Jones
Katayoon Kasaian
Darlene Lee
Yussanne Ma
Marco A. Marra
Michael Mayo
Richard A. Moore
Andrew J. Mungall
Karen Mungall
A. Gordon Robertson
Sara Sadeghi
Jacqueline E. Schein
Payal Sipahimalani
Angela Tam
Nina Thiessen
Kane Tse
Tina Wong
Ashton C. Berger
Rameen Beroukhim
Carrie Cibulskis
Stacey B. Gabriel
Gavin Ha
Matthew Meyerson
Steven E. Schumacher
Juliann Shih
Melanie H. Kucherlapati
Raju S. Kucherlapati
Stephen Baylin
Leslie Cope
Ludmila Danilova
Moiz S. Bootwalla
Phillip H. Lai
Dennis T. Maglinte
David J. Van Den Berg
Daniel J. Weisenberger
J. Todd Auman
Saianand Balu
Tom Bodenheimer
Cheng Fan
Katherine A. Hoadley
Alan P. Hoyle
Stuart R. Jefferys
Corbin D. Jones
Shaowu Meng
Piotr A. Mieczkowski
Lisle E. Mose
Amy H. Perou
Charles M. Perou
Jeffrey Roach
Yan Shi
Janae V. Simons
Tara Skelly
Matthew G. Soloway
Donghui Tan
Umadevi Veluvolu
Toshinori Hinoue
Wanding Zhou
Michelle Bellair
Kyle Chang
Kyle Covington
Chad J. Creighton
Huyen Dinh
HarshaVardhan Doddapaneni
Jennifer Drummond
Richard A. Gibbs
Robert Glenn
Walker Hale
Yi Han
Jianhong Hu
Viktoriya Korchina
Sandra Lee
Lora Lewis
Wei Li
Xiuping Liu
Margaret Morgan
Donna Morton
Donna Muzny
Jireh Santibanez
Margi Sheth
Min Wang
Liu Xi
Fengmei Zhao
Julian Hess
Elizabeth L. Appelbaum
Matthew Bailey
Matthew G. Cordes
Catrina C. Fronick
Lucinda A. Fulton
Robert S. Fulton
Cyriac Kandoth
Elaine R. Mardis
Michael D. McLellan
Christopher A. Miller
Heather K. Schmidt
Richard K. Wilson
Daniel Crain
Erin Curley
Johanna Gardner
Kevin Lau
David Mallery
Scott Morris
Joseph Paulauskis
Robert Penny
Candace Shelton
Troy Shelton
Mark Sherman
Eric Thompson
Peggy Yena
Jay Bowen
Julie M. Gastier-Foster
Mark Gerken
Kristen M. Leraas
Tara M. Lichtenberg
Nilsa C. Ramirez
Lisa Wise
Erik Zmuda
Niall Corcoran
Tony Costello
Christopher Hovens
Andre L. Carvalho
Ana C. de Carvalho
José H. Fregnani
Adhemar Longatto-Filho
Rui M. Reis
Cristovam Scapulatempo-Neto
Henrique C.S. Silveira
Daniel O. Vidal
Andrew Burnette
Jennifer Eschbacher
Beth Hermes
Ardene Noss
Rosy Singh
Matthew L. Anderson
Patricia D. Castro
Michael Ittmann
David Huntsman
Bernard Kohl
Xuan Le
Richard Thorp
Chris Andry
Elizabeth R. Duffy
Vladimir Lyadov
Oxana Paklina
Galiya Setdikova
Alexey Shabunin
Mikhail Tavobilov
Christopher McPherson
Ronald Warnick
Ross Berkowitz
Daniel Cramer
Colleen Feltmate
Neil Horowitz
Adam Kibel
Michael Muto
Chandrajit P. Raut
Andrei Malykh
Jill S. Barnholtz-Sloan
Wendi Barrett
Karen Devine
Jordonna Fulop
Quinn T. Ostrom
Kristen Shimmel
Yingli Wolinsky
Andrew E. Sloan
Agostino De Rose
Felice Giuliante
Marc Goodman
Beth Y. Karlan
Curt H. Hagedorn
John Eckman
Jodi Harr
Jerome Myers
Kelinda Tucker
Leigh Anne Zach
Brenda Deyarmin
Leonid Kvecher
Caroline Larson
Richard J. Mural
Stella Somiari
Ales Vicha
Tomas Zelinka
Joseph Bennett
Mary Iacocca
Brenda Rabeno
Patricia Swanson
Mathieu Latour
Louis Lacombe
Bernard Têtu
Alain Bergeron
Mary McGraw
Susan M. Staugaitis
John Chabot
Hanina Hibshoosh
Antonia Sepulveda
Tao Su
Timothy Wang
Olga Potapova
Olga Voronina
Laurence Desjardins
Odette Mariani
Sergio Roman-Roman
Xavier Sastre
Marc-Henri Stern
Feixiong Cheng
Sabina Signoretti
Andrew Berchuck
Darell Bigner
Eric Lipp
Jeffrey Marks
Shannon McCall
Roger McLendon
Angeles Secord
Alexis Sharp
Madhusmita Behera
Daniel J. Brat
Amy Chen
Keith Delman
Seth Force
Fadlo Khuri
Kelly Magliocca
Shishir Maithel
Jeffrey J. Olson
Taofeek Owonikoko
Alan Pickens
Suresh Ramalingam
Dong M. Shin
Gabriel Sica
Erwin G. Van Meir
Hongzheng Zhang
Wil Eijckenboom
Ad Gillis
Esther Korpershoek
Leendert Looijenga
Wolter Oosterhuis
Hans Stoop
Kim E. van Kessel
Ellen C. Zwarthoff
Chiara Calatozzolo
Lucia Cuppini
Stefania Cuzzubbo
Francesco DiMeco
Gaetano Finocchiaro
Luca Mattei
Alessandro Perin
Bianca Pollo
Chu Chen
John Houck
Pawadee Lohavanichbutr
Arndt Hartmann
Christine Stoehr
Robert Stoehr
Helge Taubert
Sven Wach
Bernd Wullich
Witold Kycler
Dawid Murawa
Maciej Wiznerowicz
Ki Chung
W. Jeffrey Edenfield
Julie Martin
Eric Baudin
Glenn Bubley
Raphael Bueno
Assunta De Rienzo
William G. Richards
Steven Kalkanis
Tom Mikkelsen
Houtan Noushmehr
Lisa Scarpace
Nicolas Girard
Marta Aymerich
Elias Campo
Eva Giné
Armando López Guillermo
Nguyen Van Bang
Phan Thi Hanh
Bui Duc Phu
Yufang Tang
Howard Colman
Kimberley Evason
Peter R. Dottino
John A. Martignetti
Hani Gabra
Hartmut Juhl
Teniola Akeredolu
Serghei Stepa
Dave Hoon
Keunsoo Ahn
Koo Jeong Kang
Felix Beuschlein
Anne Breggia
Michael Birrer
Debra Bell
Mitesh Borad
Alan H. Bryce
Erik Castle
Vishal Chandan
John Cheville
John A. Copland
Michael Farnell
Thomas Flotte
Nasra Giama
Thai Ho
Michael Kendrick
Jean-Pierre Kocher
Karla Kopp
Catherine Moser
David Nagorney
Daniel O’Brien
Brian Patrick O’Neill
Tushar Patel
Gloria Petersen
Florencia Que
Michael Rivera
Lewis Roberts
Robert Smallridge
Thomas Smyrk
Melissa Stanton
R. Houston Thompson
Michael Torbenson
Ju Dong Yang
Lizhi Zhang
Fadi Brimo
Jaffer A. Ajani
Ana Maria Angulo Gonzalez
Carmen Behrens
Jolanta Bondaruk
Russell Broaddus
Bogdan Czerniak
Bita Esmaeli
Junya Fujimoto
Jeffrey Gershenwald
Charles Guo
Alexander J. Lazar
Christopher Logothetis
Funda Meric-Bernstam
Cesar Moran
Lois Ramondetta
David Rice
Anil Sood
Pheroze Tamboli
Timothy Thompson
Patricia Troncoso
Anne Tsao
Ignacio Wistuba
Candace Carter
Lauren Haydu
Peter Hersey
Valerie Jakrot
Hojabr Kakavand
Richard Kefford
Kenneth Lee
Georgina Long
Graham Mann
Michael Quinn
Robyn Saw
Richard Scolyer
Kerwin Shannon
Andrew Spillane
Jonathan Stretch
Maria Synott
John Thompson
James Wilmott
Hikmat Al-Ahmadie
Timothy A. Chan
Ronald Ghossein
Anuradha Gopalan
Douglas A. Levine
Victor Reuter
Samuel Singer
Bhuvanesh Singh
Nguyen Viet Tien
Thomas Broudy
Cyrus Mirsaidi
Praveen Nair
Paul Drwiega
Judy Miller
Jennifer Smith
Howard Zaren
Joong-Won Park
Nguyen Phi Hung
Electron Kebebew
W. Marston Linehan
Adam R. Metwalli
Karel Pacak
Peter A. Pinto
Mark Schiffman
Laura S. Schmidt
Cathy D. Vocke
Nicolas Wentzensen
Robert Worrell
Hannah Yang
Marc Moncrieff
Chandra Goparaju
Jonathan Melamed
Harvey Pass
Natalia Botnariuc
Irina Caraman
Mircea Cernat
Inga Chemencedji
Adrian Clipca
Serghei Doruc
Ghenadie Gorincioi
Sergiu Mura
Maria Pirtac
Irina Stancul
Diana Tcaciuc
Monique Albert
Iakovina Alexopoulou
Angel Arnaout
John Bartlett
Jay Engel
Sebastien Gilbert
Jeremy Parfitt
Harman Sekhon
George Thomas
Doris M. Rassl
Robert C. Rintoul
Carlo Bifulco
Raina Tamakawa
Walter Urba
Nicholas Hayward
Henri Timmers
Anna Antenucci
Francesco Facciolo
Gianluca Grazi
Mirella Marino
Roberta Merola
Ronald de Krijger
Anne-Paule Gimenez-Roqueplo
Alain Piché
Simone Chevalier
Ginette McKercher
Kivanc Birsoy
Gene Barnett
Cathy Brewer
Carol Farver
Theresa Naska
Nathan A. Pennell
Daniel Raymond
Cathy Schilero
Kathy Smolenski
Felicia Williams
Carl Morrison
Jeffrey A. Borgia
Michael J. Liptay
Mark Pool
Christopher W. Seder
Kerstin Junker
Larsson Omberg
Mikhail Dinkin
George Manikhas
Domenico Alvaro
Maria Consiglia Bragazzi
Vincenzo Cardinale
Guido Carpino
Eugenio Gaudio
David Chesla
Sandra Cottingham
Michael Dubina
Fedor Moiseenko
Renumathy Dhanasekaran
Karl-Friedrich Becker
Klaus-Peter Janssen
Julia Slotta-Huspenina
Mohamed H. Abdel-Rahman
Dina Aziz
Sue Bell
Colleen M. Cebulla
Amy Davis
Rebecca Duell
J. Bradley Elder
Joe Hilty
Bahavna Kumar
James Lang
Norman L. Lehman
Randy Mandt
Phuong Nguyen
Robert Pilarski
Karan Rai
Lynn Schoenfield
Kelly Senecal
Paul Wakely
Paul Hansen
Ronald Lechan
James Powers
Arthur Tischler
William E. Grizzle
Katherine C. Sexton
Alison Kastl
Joel Henderson
Sima Porten
Jens Waldmann
Martin Fassnacht
Sylvia L. Asa
Dirk Schadendorf
Marta Couce
Markus Graefen
Hartwig Huland
Guido Sauter
Thorsten Schlomm
Ronald Simon
Pierre Tennstedt
Oluwole Olabode
Mark Nelson
Oliver Bathe
Peter R. Carroll
June M. Chan
Philip Disaia
Pat Glenn
Robin K. Kelley
Charles N. Landen
Joanna Phillips
Michael Prados
Jeffry Simko
Karen Smith-McCune
Scott VandenBerg
Kevin Roggin
Ashley Fehrenbach
Ady Kendler
Suzanne Sifri
Ruth Steele
Antonio Jimeno
Francis Carey
Ian Forgie
Massimo Mannelli
Michael Carney
Brenda Hernandez
Benito Campos
Christel Herold-Mende
Christin Jungk
Andreas Unterberg
Andreas von Deimling
Aaron Bossler
Joseph Galbraith
Laura Jacobus
Michael Knudson
Tina Knutson
Deqin Ma
Mohammed Milhem
Rita Sigmund
Andrew K. Godwin
Rashna Madan
Howard G. Rosenthal
Clement Adebamowo
Sally N. Adebamowo
Alex Boussioutas
David Beer
Thomas Giordano
Anne-Marie Mes-Masson
Fred Saad
Therese Bocklage
Lisa Landrum
Robert Mannel
Kathleen Moore
Katherine Moxley
Russel Postier
Joan Walker
Rosemary Zuna
Michael Feldman
Federico Valdivieso
Rajiv Dhir
James Luketich
Edna M. Mora Pinero
Mario Quintero-Aguilo
Carlos Gilberto Carlotti, Jr.
Jose Sebastião Dos Santos
Rafael Kemp
Ajith Sankarankuty
Daniela Tirapelli
James Catto
Kathy Agnew
Elizabeth Swisher
Jenette Creaney
Bruce Robinson
Carl Simon Shelley
Eryn M. Godwin
Sara Kendall
Cassaundra Shipman
Carol Bradford
Thomas Carey
Andrea Haddad
Jeffey Moyer
Lisa Peterson
Mark Prince
Laura Rozek
Gregory Wolf
Rayleen Bowman
Kwun M. Fong
Ian Yang
Robert Korst
W. Kimryn Rathmell
J. Leigh Fantacone-Campbell
Jeffrey A. Hooke
Albert J. Kovatich
Craig D. Shriver
John DiPersio
Bettina Drake
Ramaswamy Govindan
Sharon Heath
Timothy Ley
Brian Van Tine
Peter Westervelt
Mark A. Rubin
Jung Il Lee
Natália D. Aredes
Armaz Mariamidze
Source :
Cell Reports, Vol 23, Iss 1, Pp 239-254.e6 (2018)
Publication Year :
2018
Publisher :
Elsevier, 2018.

Abstract

Summary: DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy. : Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores. Keywords: The Cancer Genome Atlas PanCanAtlas project, DNA damage repair, somatic mutations, somatic copy-number alterations, epigenetic silencing, DNA damage footprints, mutational signatures, integrative statistical analysis, protein structure analysis

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
22111247
Volume :
23
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.08064f6f4104b4d968f65a126a095ce
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2018.03.076