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

Syed Hassan Ejaz Zaidi(Ontario Institute for Cancer Research), Tabitha A. Harrison(Fred Hutch Cancer Center), Amanda I. Phipps(Fred Hutch Cancer Center), Robert S. Steinfelder(Fred Hutch Cancer Center), Quang M. Trinh(Ontario Institute for Cancer Research), Conghui Qu(Fred Hutch Cancer Center), Barbara L. Banbury(Fred Hutch Cancer Center), Peter Georgeson(The University of Melbourne), Catherine S. Grasso(Cedars-Sinai Medical Center), Marios Giannakis(Broad Institute), Jeremy Adams(Ontario Institute for Cancer Research), Elizabeth Alwers(German Cancer Research Center), Efrat L. Amitay(German Cancer Research Center), Richard Barfield(University of Washington), Sonja I. Berndt(National Institutes of Health), Ivan Borozan(Ontario Institute for Cancer Research), Hermann Brenner(German Cancer Research Center), Stefanie Brezina(Medical University of Vienna), Daniel D. Buchanan(The Royal Melbourne Hospital), Yin Cao(Harvard University), Andrew T. Chan(Broad Institute), Jenny Chang‐Claude(Universität Hamburg), Charles M. Connolly(Fred Hutch Cancer Center), David A. Drew(Harvard University), Alton B. Farris(Emory University), Jane C. Figueiredo(University of Southern California), Amy J. French(Mayo Clinic), Charles S. Fuchs(Yale Cancer Center), Levi A. Garraway(Broad Institute), Steve Gruber(University of Southern California), Mark A. Guinter(American Cancer Society), Stanley R. Hamilton(City of Hope), Sophia Harlid(Umeå University), Lawrence E. Heisler(Ontario Institute for Cancer Research), Akihisa Hidaka(Fred Hutch Cancer Center), John L. Hopper(The University of Melbourne), Wen‐Yi Huang(National Institutes of Health), Jeroen R. Huyghe(Fred Hutch Cancer Center), 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 Hutch Cancer Center), Xuemei Luo(Ontario Institute for Cancer Research), Elaine R. Mardis(Nationwide Children's Hospital), John D. McPherson(Ontario Institute for Cancer Research), Jessica K. Miller(Ontario Institute for Cancer Research), Vı́ctor Moreno(Institut d'Investigació Biomédica de Bellvitge), Xinmeng Jasmine Mu(Broad Institute), Reiko Nishihara(Brigham and Women's Hospital), Nickolas Papadopoulos(Sidney Kimmel Comprehensive Cancer Center), Danielle Pasternack(Ontario Institute for Cancer Research), Michael J. Quist(Fred Hutch Cancer Center), Adilya Rafikova(Ontario Institute for Cancer Research), Emma Reid(Ontario Institute for Cancer Research), Eve Shinbrot(Baylor College of Medicine), Brian H. Shirts(University of Washington Medical Center), Lincoln Stein(Ontario Institute for Cancer Research), Cherie Teney(Ontario Institute for Cancer Research), Lee E. Timms(Ontario Institute for Cancer Research), Caroline Y. Um(American Cancer Society), Bethany Van Guelpen(Umeå University), Megan Van Tassel(Ontario Institute for Cancer Research), Xiaolong Wang(Fred Hutch Cancer Center), David A. Wheeler(Baylor College of Medicine), Christina K. Yung(Ontario Institute for Cancer Research), Li Hsu(University of Washington), Shuji Ogino(Broad Institute), Andrea Gsur(Medical University of Vienna), Polly A. Newcomb(University of Washington), Steven Gallinger(Ontario Institute for Cancer Research), Michael Hoffmeister(German Cancer Research Center), Peter T. Campbell(American Cancer Society), Stephen N. Thibodeau(Mayo Clinic), Wei Sun(Fred Hutch Cancer Center), Thomas J. Hudson(Ontario Institute for Cancer Research), Ulrike Peters(University of Washington)
Nature Communications
July 20, 2020
10.1038/s41467-020-17386-z
Cited by 94Open Access
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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.

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