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

Author

Listed:
  • 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
    Victorian Comprehensive Cancer Centre)

  • Catherine S. Grasso

    (Fred Hutchinson Cancer Research Centre
    Cedar Sinai Medical Center)

  • Marios Giannakis

    (Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • 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
    University of Washington)

  • Sonja I. Berndt

    (National Institutes of Health)

  • Ivan Borozan

    (Ontario Institute for Cancer Research)

  • Hermann Brenner

    (German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
    German Cancer Research Center (DKFZ))

  • Stefanie Brezina

    (Medical University of Vienna)

  • Daniel D. Buchanan

    (The University of Melbourne, Parkville
    Victorian Comprehensive Cancer Centre
    The Royal Melbourne Hospital
    The University of Melbourne)

  • Yin Cao

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    Washington University School of Medicine in St. Louis)

  • Andrew T. Chan

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Jenny Chang-Claude

    (German Cancer Research Center (DKFZ)
    University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH))

  • Charles M. Connolly

    (Fred Hutchinson Cancer Research Centre)

  • David A. Drew

    (Massachusetts General Hospital and Harvard Medical School
    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
    University of Southern California)

  • Amy J. French

    (Mayo Clinic)

  • Charles S. Fuchs

    (Yale Cancer Center
    Yale School of Medicine
    Smilow Cancer Hospital)

  • Levi A. Garraway

    (Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • 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
    UC Davis School of Medicine)

  • Jessica K. Miller

    (Ontario Institute for Cancer Research)

  • Victor Moreno

    (Catalan Institute of Oncology and ONCOBELL Program, IDIBELL
    CIBER Epidemiología y Salud Pública (CIBERESP)
    University of Barcelona)

  • Xinmeng Jasmine Mu

    (Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Reiko Nishihara

    (Dana-Farber Cancer Institute and Harvard Medical School
    Harvard T.H. Chan School of Public Health
    Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street)

  • 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
    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
    University of Washington)

  • Shuji Ogino

    (Broad Institute of MIT and Harvard
    Harvard University
    Dana-Farber Cancer Institute and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street)

  • Andrea Gsur

    (Medical University of Vienna)

  • Polly A. Newcomb

    (Fred Hutchinson Cancer Research Centre
    University of Washington)

  • Steven Gallinger

    (Ontario Institute for Cancer Research
    Mount Sinai Hospital, University of Toronto
    University Health Network Toronto General Hospital)

  • 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
    University of Washington)

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.

Suggested Citation

  • 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. Ad, 2020. "Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17386-z
    DOI: 10.1038/s41467-020-17386-z
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    Cited by:

    1. Peter Georgeson & Tabitha A. Harrison & Bernard J. Pope & Syed H. Zaidi & Conghui Qu & Robert S. Steinfelder & Yi Lin & Jihoon E. Joo & Khalid Mahmood & Mark Clendenning & Romy Walker & Efrat L. Amita, 2022. "Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Ori Hassin & Nishanth Belugali Nataraj & Michal Shreberk-Shaked & Yael Aylon & Rona Yaeger & Giulia Fontemaggi & Saptaparna Mukherjee & Martino Maddalena & Adi Avioz & Ortal Iancu & Giuseppe Mallel & , 2022. "Different hotspot p53 mutants exert distinct phenotypes and predict outcome of colorectal cancer patients," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Qi Zhao & Feng Wang & Yan-Xing Chen & Shifu Chen & Yi-Chen Yao & Zhao-Lei Zeng & Teng-Jia Jiang & Ying-Nan Wang & Chen-Yi Wu & Ying Jing & You-Sheng Huang & Jing Zhang & Zi-Xian Wang & Ming-Ming He & , 2022. "Comprehensive profiling of 1015 patients’ exomes reveals genomic-clinical associations in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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