Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.

Autor:	Georgeson P; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia., Steinfelder RS; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Harrison TA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Pope BJ; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.; Melbourne Bioinformatics, The University of Melbourne, Carlton, Australia., Zaidi SH; Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Qu C; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Lin Y; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Joo JE; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia., Mahmood K; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.; Melbourne Bioinformatics, The University of Melbourne, Carlton, Australia., Clendenning M; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia., Walker R; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia., Aglago EK; Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK., Berndt SI; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Brenner H; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center(DKFZ), Heidelberg, Germany.; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany., Campbell PT; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA., Cao Y; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri, USA.; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Chan AT; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA., Chang-Claude J; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany., Dimou N; Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France., Doheny KF; Center for Inherited Disease Research (CIDR), Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Drew DA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Figueiredo JC; Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., French AJ; Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA., Gallinger S; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.; Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Giannakis M; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Giles GG; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia., Goode EL; Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, Minnesota, USA., Gruber SB; Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte CA, USA., Gsur A; Center for Cancer Research, Medical University Vienna, Vienna, Austria., Gunter MJ; Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France., Harlid S; Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden., Hoffmeister M; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany., Hsu L; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; Department of Biostatistics, University of Washington, Seattle, Washington, USA., Huang WY; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Huyghe JR; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Manson JE; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Moreno V; Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.; ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.; Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, 08908 Barcelona, Spain., Murphy N; Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France., Nassir R; Department of Pathology, College of Medicine, Umm Al-Qura University, Saudi Arabia., Newton CC; Department of Population Science, American Cancer Society, Atlanta, Georgia., Nowak JA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Obón-Santacana M; Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.; ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Ogino S; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Cancer Immunology Program, Dana-Farber Harvard Cancer Center, Boston, Massachusetts, USA., Pai RK; Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA., Papadimitrou N; Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France., Potter JD; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; Research Centre for Hauora and Health, Massey University, Wellington, New Zealand., Schoen RE; Departments of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA., Song M; Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.; Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA., Sun W; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Toland AE; Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA., Trinh QM; Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Tsilidis K; Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK., Ugai T; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Um CY; Department of Population Science, American Cancer Society, Atlanta, Georgia, USA., Macrae FA; Parkville Familial Cancer Centre, and Dept of Colorectal Medicine and Genetics The Royal Melbourne Hospital.; Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Australia.; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia., Rosty C; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.; Envoi Specialist Pathologists, Brisbane, Australia.; University of Queensland, Brisbane, Australia., Hudson TJ; Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Winship IM; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia.; Department of Medicine, The University of Melbourne, Parkville, Australia., Phipps AI; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; Department of Epidemiology, University of Washington, Seattle, Washington, USA., Jenkins MA; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia., Peters U; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; Department of Epidemiology, University of Washington, Seattle, Washington, USA., Buchanan DD; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Jan 30. Date of Electronic Publication: 2024 Jan 30.
DOI:	10.1101/2023.03.10.23287127
Abstrakt:	Background and Aims: The microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain of Escherichia coli harboring the pks island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown. Methods: SBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival. Results: In total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5x10 -28 ). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1x10 -5 ) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6x10 -6 ) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was the APC :c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3x10 -80 ). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88-positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage. Conclusion: SBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC. Competing Interests: Competing Interests Dr. Marios Giannakis received research funding from Servier and Janssen, unrelated to this study. Dr. Stephen B Gruber co-founded Brogent International LLC, unrelated to this study. Dr. Jonathan A. Nowak received research support from Akoya Biosciences, Illumina, and NanoString, unrelated to this study. Dr. Rish K. Pai received consultant income from Alimentiv Inc., Allergan, Eli Lilly, and AbbVie, unrelated to this study. Dr. Robert E. Schoen received research support from Freenome, Immunovia, and Exact Sciences, unrelated to this study. All other authors declare no competing interests.
Databáze:	MEDLINE
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