Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Cell Reports. 2018;23(1):282-296.e4

 

Journal Homepage

Journal Title: Cell Reports

ISSN: 2211-1247 (Online)

Publisher: Elsevier

LCC Subject Category: Science: Biology (General)

Country of publisher: Netherlands

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS

Michael Seiler (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA)
Shouyong Peng (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA)
Anant A. Agrawal (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA)
James Palacino (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA)
Teng Teng (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA)
Ping Zhu (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA)
Peter G. Smith (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA)
Silvia Buonamici (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA; Corresponding author)
Lihua Yu (H3 Biomedicine, Inc., 300 Technology Square, Cambridge, MA 02139, USA; Corresponding author)
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
Nyasha Chambwe
Varsha Dhankani
Theo Knijnenburg
Roger Kramer
Kalle Leinonen
Yuexin Liu
Michael Miller
Sheila Reynolds
Ilya Shmulevich
Vesteinn Thorsson
Wei Zhang
Rehan Akbani
Bradley M. Broom
Apurva M. Hegde
Zhenlin Ju
Rupa S. Kanchi
Anil Korkut
Jun Li
Han Liang
Shiyun Ling
Wenbin Liu
Yiling Lu
Gordon B. Mills
Kwok-Shing Ng
Arvind Rao
Michael Ryan
Jing Wang
John N. Weinstein
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
Christina Yau
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
Andrew D. Cherniack
Carrie Cibulskis
Stacey B. Gabriel
Galen F. Gao
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
Huihui Fan
Toshinori Hinoue
Peter W. Laird
Hui Shen
Wanding Zhou
Michelle Bellair
Kyle Chang
Kyle Covington
Chad J. Creighton
Huyen Dinh
HarshaVardhan Doddapaneni
Lawrence A. Donehower
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
Eve Shinbrot
Linghua Wang
Min Wang
David A. Wheeler
Liu Xi
Fengmei Zhao
Julian Hess
Elizabeth L. Appelbaum
Matthew Bailey
Matthew G. Cordes
Li Ding
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
Hai Hu
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
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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
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Harvey Pass
Natalia Botnariuc
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Serghei Doruc
Ghenadie Gorincioi
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Maria Pirtac
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Monique Albert
Iakovina Alexopoulou
Angel Arnaout
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Sebastien Gilbert
Jeremy Parfitt
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George Thomas
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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
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Norman L. Lehman
Randy Mandt
Phuong Nguyen
Robert Pilarski
Karan Rai
Lynn Schoenfield
Kelly Senecal
Paul Wakely
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Ronald Lechan
James Powers
Arthur Tischler
William E. Grizzle
Katherine C. Sexton
Alison Kastl
Joel Henderson
Sima Porten
Jens Waldmann
Martin Fassnacht
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Hartwig Huland
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Thorsten Schlomm
Ronald Simon
Pierre Tennstedt
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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
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Mohammed Milhem
Rita Sigmund
Andrew K. Godwin
Rashna Madan
Howard G. Rosenthal
Clement Adebamowo
Sally N. Adebamowo
Alex Boussioutas
David Beer
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Anne-Marie Mes-Masson
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Federico Valdivieso
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Edna M. Mora Pinero
Mario Quintero-Aguilo
Carlos Gilberto Carlotti, Jr.
Jose Sebastião Dos Santos
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Ajith Sankarankuty
Daniela Tirapelli
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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

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 31 weeks

 

Abstract | Full Text

Summary: Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis. : Seiler et al. report that 119 splicing factor genes carry putative driver mutations over 33 tumor types in TCGA. The most common mutations appear to be mutually exclusive and are associated with lineage-independent altered splicing. Samples with these mutations show deregulation of cell-autonomous pathways and immune infiltration. Keywords: splicing, SF3B1, U2AF1, SRSF2, RBM10, FUBP1, cancer, mutation