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Individuals exposed to pks+ Escherichia coli may have an increased risk of colorectal cancer (CRC), which suggests that treating this genotoxic strain could potentially reduce risk of CRC, according to investigators.
While previous studies have demonstrated associations between various intestinal bacteria and CRC, this is the first study to show a direct link between exposure to a particular strain of bacteria and a unique mutational signature, reported lead author Cayetano Pleguezuelos-Manzano, of the Hubrecht Institute in Utrecht, Netherlands.
Recent studies showed that colibactin, a toxin produced by pks+ E. coli, causes a specific type of DNA damage, although the outcome of this damage remained unclear, the investigators wrote in Nature.
To look for a possible mutational signature resulting from this damage, the investigators used human intestinal organoids, which were established from primary crypt stem cells. A pks+ E. coli strain was microinjected into one group of organoids, while another E. coli strain (pks∆clbQ), which does not produce colibactin, was injected into a second group.
Immunofluorescence showed that the organoids exposed to the pks+ E. coli strain developed characteristic DNA damage, whereas the control group did not.
Next, the investigators repeatedly injected organoids with either pks+ E. coli, pks∆clbQ, or dye only. This experiment was conducted for 5 months to achieve long-term exposure. Whole genome sequencing showed that the pks+ E. coli group developed two unique mutational signatures: a single-base substitution (SBS-pks) and a small indel signature (ID-pks). Neither of the other two groups developed these signatures, which suggests that they were a direct consequence of exposure to pks+ E. coli.
To determine the prevalence of such mutational signatures in human patients, the investigators looked for the SBS-pks and ID-pks signatures in 5,876 human cancer genomes. One analysis involving 496 CRC metastases showed strong enrichment of both signatures, compared with other cancer types (P less than .0001). Another analysis involving 2,208 CRC tumors found that 5.0% and 4.4% of patients had SBS-pks and ID-pks enrichment, respectively.
“This study implies that detection and removal of pks+ E. coli, as well as re-evaluation of probiotic strains harboring the pks island, could decrease the risk of cancer in a large group of individuals,” the investigators concluded.
The study was funded by the Ministry of Education, Culture and Science of the government of the Netherlands. The investigators reported additional relationships with OrigiMed, Bayer, Janssen, and others.
SOURCE: Pleguezuelos-Manzano C et al. Nature. 2020 Feb 27. doi: 10.1038/s41586-020-2080-8.
Individuals exposed to pks+ Escherichia coli may have an increased risk of colorectal cancer (CRC), which suggests that treating this genotoxic strain could potentially reduce risk of CRC, according to investigators.
While previous studies have demonstrated associations between various intestinal bacteria and CRC, this is the first study to show a direct link between exposure to a particular strain of bacteria and a unique mutational signature, reported lead author Cayetano Pleguezuelos-Manzano, of the Hubrecht Institute in Utrecht, Netherlands.
Recent studies showed that colibactin, a toxin produced by pks+ E. coli, causes a specific type of DNA damage, although the outcome of this damage remained unclear, the investigators wrote in Nature.
To look for a possible mutational signature resulting from this damage, the investigators used human intestinal organoids, which were established from primary crypt stem cells. A pks+ E. coli strain was microinjected into one group of organoids, while another E. coli strain (pks∆clbQ), which does not produce colibactin, was injected into a second group.
Immunofluorescence showed that the organoids exposed to the pks+ E. coli strain developed characteristic DNA damage, whereas the control group did not.
Next, the investigators repeatedly injected organoids with either pks+ E. coli, pks∆clbQ, or dye only. This experiment was conducted for 5 months to achieve long-term exposure. Whole genome sequencing showed that the pks+ E. coli group developed two unique mutational signatures: a single-base substitution (SBS-pks) and a small indel signature (ID-pks). Neither of the other two groups developed these signatures, which suggests that they were a direct consequence of exposure to pks+ E. coli.
To determine the prevalence of such mutational signatures in human patients, the investigators looked for the SBS-pks and ID-pks signatures in 5,876 human cancer genomes. One analysis involving 496 CRC metastases showed strong enrichment of both signatures, compared with other cancer types (P less than .0001). Another analysis involving 2,208 CRC tumors found that 5.0% and 4.4% of patients had SBS-pks and ID-pks enrichment, respectively.
“This study implies that detection and removal of pks+ E. coli, as well as re-evaluation of probiotic strains harboring the pks island, could decrease the risk of cancer in a large group of individuals,” the investigators concluded.
The study was funded by the Ministry of Education, Culture and Science of the government of the Netherlands. The investigators reported additional relationships with OrigiMed, Bayer, Janssen, and others.
SOURCE: Pleguezuelos-Manzano C et al. Nature. 2020 Feb 27. doi: 10.1038/s41586-020-2080-8.
Individuals exposed to pks+ Escherichia coli may have an increased risk of colorectal cancer (CRC), which suggests that treating this genotoxic strain could potentially reduce risk of CRC, according to investigators.
While previous studies have demonstrated associations between various intestinal bacteria and CRC, this is the first study to show a direct link between exposure to a particular strain of bacteria and a unique mutational signature, reported lead author Cayetano Pleguezuelos-Manzano, of the Hubrecht Institute in Utrecht, Netherlands.
Recent studies showed that colibactin, a toxin produced by pks+ E. coli, causes a specific type of DNA damage, although the outcome of this damage remained unclear, the investigators wrote in Nature.
To look for a possible mutational signature resulting from this damage, the investigators used human intestinal organoids, which were established from primary crypt stem cells. A pks+ E. coli strain was microinjected into one group of organoids, while another E. coli strain (pks∆clbQ), which does not produce colibactin, was injected into a second group.
Immunofluorescence showed that the organoids exposed to the pks+ E. coli strain developed characteristic DNA damage, whereas the control group did not.
Next, the investigators repeatedly injected organoids with either pks+ E. coli, pks∆clbQ, or dye only. This experiment was conducted for 5 months to achieve long-term exposure. Whole genome sequencing showed that the pks+ E. coli group developed two unique mutational signatures: a single-base substitution (SBS-pks) and a small indel signature (ID-pks). Neither of the other two groups developed these signatures, which suggests that they were a direct consequence of exposure to pks+ E. coli.
To determine the prevalence of such mutational signatures in human patients, the investigators looked for the SBS-pks and ID-pks signatures in 5,876 human cancer genomes. One analysis involving 496 CRC metastases showed strong enrichment of both signatures, compared with other cancer types (P less than .0001). Another analysis involving 2,208 CRC tumors found that 5.0% and 4.4% of patients had SBS-pks and ID-pks enrichment, respectively.
“This study implies that detection and removal of pks+ E. coli, as well as re-evaluation of probiotic strains harboring the pks island, could decrease the risk of cancer in a large group of individuals,” the investigators concluded.
The study was funded by the Ministry of Education, Culture and Science of the government of the Netherlands. The investigators reported additional relationships with OrigiMed, Bayer, Janssen, and others.
SOURCE: Pleguezuelos-Manzano C et al. Nature. 2020 Feb 27. doi: 10.1038/s41586-020-2080-8.
FROM NATURE