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Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.
Georgeson, Peter; Steinfelder, Robert S; Harrison, Tabitha A; Pope, Bernard J; Zaidi, Syed H; Qu, Conghui; Lin, Yi; Joo, Jihoon E; Mahmood, Khalid; Clendenning, Mark; Walker, Romy; Aglago, Elom K; Berndt, Sonja I; Brenner, Hermann; Campbell, Peter T; Cao, Yin; Chan, Andrew T; Chang-Claude, Jenny; Dimou, Niki; Doheny, Kimberly F; Drew, David A; Figueiredo, Jane C; French, Amy J; Gallinger, Steven; Giannakis, Marios; Giles, Graham G; Goode, Ellen L; Gruber, Stephen B; Gsur, Andrea; Gunter, Marc J; Harlid, Sophia; Hoffmeister, Michael; Hsu, Li; Huang, Wen-Yi; Huyghe, Jeroen R; Manson, JoAnn E; Moreno, Victor; Murphy, Neil; Nassir, Rami; Newton, Christina C; Nowak, Jonathan A; Obón-Santacana, Mireia; Ogino, Shuji; Pai, Rish K; Papadimitrou, Nikos; Potter, John D; Schoen, Robert E; Song, Mingyang; Sun, Wei; Toland, Amanda E.
Afiliação
  • Georgeson P; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
  • Steinfelder RS; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
  • Harrison TA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Pope BJ; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Zaidi SH; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
  • Qu C; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
  • Lin Y; Melbourne Bioinformatics, The University of Melbourne, Carlton, Australia.
  • Joo JE; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Mahmood K; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Clendenning M; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Walker R; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
  • Aglago EK; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
  • Berndt SI; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
  • Brenner H; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
  • Campbell PT; Melbourne Bioinformatics, The University of Melbourne, Carlton, Australia.
  • Cao Y; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
  • Chan AT; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
  • Chang-Claude J; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
  • Dimou N; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
  • Doheny KF; Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
  • Drew DA; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Figueiredo JC; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • French AJ; German Cancer Consortium (DKTK), German Cancer Research Center(DKFZ), Heidelberg, Germany.
  • Gallinger S; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Giannakis M; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Giles GG; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri, USA.
  • Goode EL; Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.
  • Gruber SB; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
  • Gsur A; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Gunter MJ; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Harlid S; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Hoffmeister M; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Hsu L; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Huang WY; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
  • Huyghe JR; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Manson JE; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
  • Moreno V; Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Murphy N; Center for Inherited Disease Research (CIDR), Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Nassir R; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Newton CC; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Nowak JA; Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Obón-Santacana M; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Ogino S; Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
  • Pai RK; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Papadimitrou N; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Potter JD; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Schoen RE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Song M; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Sun W; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • Toland AE; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
medRxiv ; 2024 Jan 30.
Article em En | MEDLINE | ID: mdl-37090539
ABSTRACT
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 APCc.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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies / Risk_factors_studies Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies / Risk_factors_studies Idioma: En Ano de publicação: 2024 Tipo de documento: Article