Mutational signature in colorectal cancer caused by genotoxic pks + E. coli.

Autor: Pleguezuelos-Manzano C; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Puschhof J; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Rosendahl Huber A; Oncode Institute, Utrecht, The Netherlands.; The Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., van Hoeck A; Oncode Institute, Utrecht, The Netherlands.; Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands., Wood HM; Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK., Nomburg J; Graduate Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Gurjao C; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Manders F; Oncode Institute, Utrecht, The Netherlands.; The Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Dalmasso G; University Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH, Clermont-Ferrand, France., Stege PB; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., Paganelli FL; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., Geurts MH; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Beumer J; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands., Mizutani T; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Miao Y; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., van der Linden R; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands., van der Elst S; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands., Garcia KC; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA., Top J; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., Willems RJL; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands., Giannakis M; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bonnet R; University Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH, Clermont-Ferrand, France.; Department of Bacteriology, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France., Quirke P; Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK., Meyerson M; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Genetics, Harvard Medical School, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Cuppen E; Oncode Institute, Utrecht, The Netherlands.; Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands.; Hartwig Medical Foundation, Amsterdam, The Netherlands.; CPCT Consortium, Rotterdam, The Netherlands., van Boxtel R; Oncode Institute, Utrecht, The Netherlands. R.vanBoxtel@prinsesmaximacentrum.nl.; The Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. R.vanBoxtel@prinsesmaximacentrum.nl., Clevers H; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, The Netherlands. h.clevers@hubrecht.eu.; Oncode Institute, Utrecht, The Netherlands. h.clevers@hubrecht.eu.; The Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. h.clevers@hubrecht.eu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Apr; Vol. 580 (7802), pp. 269-273. Date of Electronic Publication: 2020 Feb 27.
DOI: 10.1038/s41586-020-2080-8
Abstrakt: Various species of the intestinal microbiota have been associated with the development of colorectal cancer 1,2 , but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin 3 . This compound is believed to alkylate DNA on adenine residues 4,5 and induces double-strand breaks in cultured cells 3 . Here we expose human intestinal organoids to genotoxic pks + E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.
Databáze: MEDLINE
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