Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

Syed H. Zaidi, Tabitha A. Harrison, Amanda I. Phipps, Robert Steinfelder, Quang M. Trinh, Conghui Qu, Barbara L. Banbury, Peter Georgeson, Catherine S. Grasso, Marios Giannakis, Jeremy B. Adams, Elizabeth Alwers, Efrat L. Amitay, Richard T. Barfield, Sonja I. Berndt, Ivan Borozan, Hermann Brenner, Stefanie Brezina, Daniel D. Buchanan, Yin Cao, Andrew T. Chan, Jenny Chang-Claude, Charles M. Connolly, David A. Drew, Alton Brad Farris, Jane C. Figueiredo, Amy J. French, Charles S. Fuchs, Levi A. Garraway, Steve Gruber, Mark A. Guinter, Stanley R. Hamilton, Sophia Harlid, Lawrence E. Heisler, Akihisa Hidaka, John L. Hopper, Wen-Yi Huang, Jeroen R. Huyghe, Mark A. Jenkins, Paul M. Krzyzanowski, Mathieu Lemire, Yi Lin, Xuemei Luo, Elaine R. Mardis, John D. McPherson, Jessica K. Miller, Victor Moreno, Xinmeng Jasmine Mu, Reiko Nishihara, Nickolas Papadopoulos, Danielle Pasternack, Michael J. Quist, Adilya Rafikova, Emma E. G. Reid, Eve Shinbrot, Brian H. Shirts, Lincoln D. Stein, Cherie D. Teney, Lee Timms, Caroline Y. Um, Bethany Guelpen, Megan Tassel, Xiaolong Wang, David A. Wheeler, Christina K. Yung, Li Hsu, Shuji Ogino, Andrea Gsur, Polly A. Newcomb, Steven Gallinger, Michael Hoffmeister, Peter T. Campbell, Stephen N. Thibodeau, Wei Sun, Thomas J. Hudson and Ulrike Peters ()
Additional contact information
Syed H. Zaidi: Ontario Institute for Cancer Research
Tabitha A. Harrison: Fred Hutchinson Cancer Research Centre
Amanda I. Phipps: Fred Hutchinson Cancer Research Centre
Robert Steinfelder: Fred Hutchinson Cancer Research Centre
Quang M. Trinh: Ontario Institute for Cancer Research
Conghui Qu: Fred Hutchinson Cancer Research Centre
Barbara L. Banbury: Fred Hutchinson Cancer Research Centre
Peter Georgeson: The University of Melbourne, Parkville
Catherine S. Grasso: Fred Hutchinson Cancer Research Centre
Marios Giannakis: Dana-Farber Cancer Institute and Harvard Medical School
Jeremy B. Adams: Ontario Institute for Cancer Research
Elizabeth Alwers: German Cancer Research Center (DKFZ)
Efrat L. Amitay: German Cancer Research Center (DKFZ)
Richard T. Barfield: Fred Hutchinson Cancer Research Centre
Sonja I. Berndt: National Institutes of Health
Ivan Borozan: Ontario Institute for Cancer Research
Hermann Brenner: German Cancer Research Center (DKFZ)
Stefanie Brezina: Medical University of Vienna
Daniel D. Buchanan: The University of Melbourne, Parkville
Yin Cao: Massachusetts General Hospital and Harvard Medical School
Andrew T. Chan: Broad Institute of MIT and Harvard
Jenny Chang-Claude: German Cancer Research Center (DKFZ)
Charles M. Connolly: Fred Hutchinson Cancer Research Centre
David A. Drew: Massachusetts General Hospital and Harvard Medical School
Alton Brad Farris: Emory University School of Medicine
Jane C. Figueiredo: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
Amy J. French: Mayo Clinic
Charles S. Fuchs: Yale Cancer Center
Levi A. Garraway: Dana-Farber Cancer Institute and Harvard Medical School
Steve Gruber: Keck School of Medicine, University of Southern California
Mark A. Guinter: American Cancer Society
Stanley R. Hamilton: City of Hope Comprehensive Cancer Center
Sophia Harlid: Oncology Unit, Umeå University
Lawrence E. Heisler: Ontario Institute for Cancer Research
Akihisa Hidaka: Fred Hutchinson Cancer Research Centre
John L. Hopper: Victorian Comprehensive Cancer Centre
Wen-Yi Huang: National Institutes of Health
Jeroen R. Huyghe: Fred Hutchinson Cancer Research Centre
Mark A. Jenkins: The University of Melbourne
Paul M. Krzyzanowski: Ontario Institute for Cancer Research
Mathieu Lemire: Ontario Institute for Cancer Research
Yi Lin: Fred Hutchinson Cancer Research Centre
Xuemei Luo: Ontario Institute for Cancer Research
Elaine R. Mardis: Nationwide Children’s Hospital and The Ohio State University College of Medicine
John D. McPherson: Ontario Institute for Cancer Research
Jessica K. Miller: Ontario Institute for Cancer Research
Victor Moreno: Catalan Institute of Oncology and ONCOBELL Program, IDIBELL
Xinmeng Jasmine Mu: Dana-Farber Cancer Institute and Harvard Medical School
Reiko Nishihara: Dana-Farber Cancer Institute and Harvard Medical School
Nickolas Papadopoulos: Sidney Kimmel Comprehensive Cancer Center
Danielle Pasternack: Ontario Institute for Cancer Research
Michael J. Quist: Fred Hutchinson Cancer Research Centre
Adilya Rafikova: Ontario Institute for Cancer Research
Emma E. G. Reid: Ontario Institute for Cancer Research
Eve Shinbrot: Baylor College of Medicine
Brian H. Shirts: University of Washington, University of Washington Medical Center
Lincoln D. Stein: Ontario Institute for Cancer Research
Cherie D. Teney: Ontario Institute for Cancer Research
Lee Timms: Ontario Institute for Cancer Research
Caroline Y. Um: American Cancer Society
Bethany Guelpen: Oncology Unit, Umeå University
Megan Tassel: Ontario Institute for Cancer Research
Xiaolong Wang: Fred Hutchinson Cancer Research Centre
David A. Wheeler: Baylor College of Medicine
Christina K. Yung: Ontario Institute for Cancer Research
Li Hsu: Fred Hutchinson Cancer Research Centre
Shuji Ogino: Broad Institute of MIT and Harvard
Andrea Gsur: Medical University of Vienna
Polly A. Newcomb: Fred Hutchinson Cancer Research Centre
Steven Gallinger: Ontario Institute for Cancer Research
Michael Hoffmeister: German Cancer Research Center (DKFZ)
Peter T. Campbell: American Cancer Society
Stephen N. Thibodeau: Mayo Clinic
Wei Sun: Fred Hutchinson Cancer Research Centre
Thomas J. Hudson: Ontario Institute for Cancer Research
Ulrike Peters: Fred Hutchinson Cancer Research Centre

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21–0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21–1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.

Date: 2020
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DOI: 10.1038/s41467-020-17386-z

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