Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri, USA.
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
- Center for Inherited Disease Research (CIDR), Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte CA, USA.
- Center for Cancer Research, Medical University Vienna, Vienna, Austria.
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
- Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.
- Department of Pathology, College of Medicine, Umm Al-Qura University, Saudi Arabia.
- Department of Population Science, American Cancer Society, Atlanta, Georgia.
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
- Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
- Departments of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
- Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
- Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
- Department of Population Science, American Cancer Society, Atlanta, Georgia, USA.
- Parkville Familial Cancer Centre, and Dept of Colorectal Medicine and Genetics The Royal Melbourne Hospital.
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Australia.
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
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.