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

About this Publication
Title
Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival.
Pubmed ID
32686686 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Nat Commun. 2020 Jul 20; Volume 11 (Issue 1): Pages 3644
Authors
Zaidi SH, Harrison TA, Phipps AI, Steinfelder R, Trinh QM, Qu C, Banbury BL, Georgeson P, Grasso CS, Giannakis M, Adams JB, Alwers E, Amitay EL, Barfield RT, Berndt SI, Borozan I, Brenner H, Brezina S, Buchanan DD, Cao Y, ...show more Chan AT, Chang-Claude J, Connolly CM, Drew DA, Farris AB, Figueiredo JC, French AJ, Fuchs CS, Garraway LA, Gruber S, Guinter MA, Hamilton SR, Harlid S, Heisler LE, Hidaka A, Hopper JL, Huang WY, Huyghe JR, Jenkins MA, Krzyzanowski PM, Lemire M, Lin Y, Luo X, Mardis ER, McPherson JD, Miller JK, Moreno V, Mu XJ, Nishihara R, Papadopoulos N, Pasternack D, Quist MJ, Rafikova A, Reid EEG, Shinbrot E, Shirts BH, Stein LD, Teney CD, Timms L, Um CY, Van Guelpen B, Van Tassel M, Wang X, Wheeler DA, Yung CK, Hsu L, Ogino S, Gsur A, Newcomb PA, Gallinger S, Hoffmeister M, Campbell PT, Thibodeau SN, Sun W, Hudson TJ, Peters U
Affiliations
  • Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, M5G 0A3, Canada.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, 1100 Fairview Ave N, Seattle, WA, 98109, USA.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
  • Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschekagasse 8a, 1090, Vienna, Austria.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, 100 Cambridge Street, Boston, MA, 02114, USA.
  • Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
...show more
  • Pathology and Laboratory Medicine, Emory University School of Medicine, 1364 Clifton Rd. NE, Atlanta, GA, 30322, USA.
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
  • Yale Cancer Center, 333 Cedar St, New Haven, CT, 06510, USA.
  • Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, 90089, USA.
  • Behavioral and Epidemiology Research Group, American Cancer Society, 250 Williams St NW, Atlanta, GA, 30303, USA.
  • City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA, 91010, USA.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, SE-901 87, Umeå, Sweden.
  • University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
  • Institute for Genomic Medicine, Nationwide Children's Hospital and The Ohio State University College of Medicine, 575 Children's Crossroad, Columbus, OH, 43215, USA.
  • Oncology Data Analytics Program, Catalan Institute of Oncology and ONCOBELL Program, IDIBELL, Avinguda de la Granvia de l'Hospitalet 199-203, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.
  • Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
  • Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Institution, 1650 Orleans Street, Baltimore, MD, 21231, USA.
  • Human Genome Sequencing Centre, Baylor College of Medicine, One Baylor Plaza, Alkek N1419, Houston, TX, 77030, USA.
  • Department of Laboratory Medicine, University of Washington, University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA, 98195, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, 1100 Fairview Ave N, Seattle, WA, 98109, USA. upeters@fredhutch.org.
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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