Peter Georgeson, Robert S Steinfelder, Tabitha A Harrison, Bernard J Pope, Syed H Zaidi, Conghui Qu, Yi Lin, Jihoon E Joo, Khalid Mahmood, Mark Clendenning, Romy Walker, Elom K Aglago, Sonja I Berndt, Hermann Brenner, Peter T Campbell, Yin Cao, Andrew T Chan, Jenny Chang-Claude, Niki Dimou, Kimberly F Doheny, David A Drew, Jane C Figueiredo, Amy J French, Steven Gallinger, Marios Giannakis, Graham G Giles, Ellen L Goode, Stephen B Gruber, Andrea Gsur, Marc J Gunter, Sophia Harlid, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen R Huyghe, JoAnn E Manson, Victor Moreno, Neil Murphy, Rami Nassir, Christina C Newton, Jonathan A Nowak, Mireia Obón-Santacana, Shuji Ogino, Rish K Pai, Nikos Papadimitrou, John D Potter, Robert E Schoen, Mingyang Song, Wei Sun, Amanda E Toland, Quang M Trinh, Kostas Tsilidis, Tomotaka Ugai, Caroline Y Um, Finlay A Macrae, Christophe Rosty, Thomas J Hudson, Ingrid M Winship, Amanda I Phipps, Mark A Jenkins, Ulrike Peters, Daniel D Buchanan
{"title":"癌症中的基因毒性大肠杆菌素突变特征与临床病理特征、特异性基因组改变和更好的存活率有关。","authors":"Peter Georgeson, Robert S Steinfelder, Tabitha A Harrison, Bernard J Pope, Syed H Zaidi, Conghui Qu, Yi Lin, Jihoon E Joo, Khalid Mahmood, Mark Clendenning, Romy Walker, Elom K Aglago, Sonja I Berndt, Hermann Brenner, Peter T Campbell, Yin Cao, Andrew T Chan, Jenny Chang-Claude, Niki Dimou, Kimberly F Doheny, David A Drew, Jane C Figueiredo, Amy J French, Steven Gallinger, Marios Giannakis, Graham G Giles, Ellen L Goode, Stephen B Gruber, Andrea Gsur, Marc J Gunter, Sophia Harlid, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen R Huyghe, JoAnn E Manson, Victor Moreno, Neil Murphy, Rami Nassir, Christina C Newton, Jonathan A Nowak, Mireia Obón-Santacana, Shuji Ogino, Rish K Pai, Nikos Papadimitrou, John D Potter, Robert E Schoen, Mingyang Song, Wei Sun, Amanda E Toland, Quang M Trinh, Kostas Tsilidis, Tomotaka Ugai, Caroline Y Um, Finlay A Macrae, Christophe Rosty, Thomas J Hudson, Ingrid M Winship, Amanda I Phipps, Mark A Jenkins, Ulrike Peters, Daniel D Buchanan","doi":"10.1101/2023.03.10.23287127","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aims: </strong>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 <i>Escherichia coli</i> harboring the <i>pks</i> island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sup>-28</sup>). 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<sup>-5</sup>) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6x10<sup>-6</sup>) 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 <i>APC</i>:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3x10<sup>-80</sup>). 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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bd/66/nihpp-2023.03.10.23287127v1.PMC10120801.pdf","citationCount":"0","resultStr":"{\"title\":\"Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.\",\"authors\":\"Peter Georgeson, Robert S Steinfelder, Tabitha A Harrison, Bernard J Pope, Syed H Zaidi, Conghui Qu, Yi Lin, Jihoon E Joo, Khalid Mahmood, Mark Clendenning, Romy Walker, Elom K Aglago, Sonja I Berndt, Hermann Brenner, Peter T Campbell, Yin Cao, Andrew T Chan, Jenny Chang-Claude, Niki Dimou, Kimberly F Doheny, David A Drew, Jane C Figueiredo, Amy J French, Steven Gallinger, Marios Giannakis, Graham G Giles, Ellen L Goode, Stephen B Gruber, Andrea Gsur, Marc J Gunter, Sophia Harlid, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen R Huyghe, JoAnn E Manson, Victor Moreno, Neil Murphy, Rami Nassir, Christina C Newton, Jonathan A Nowak, Mireia Obón-Santacana, Shuji Ogino, Rish K Pai, Nikos Papadimitrou, John D Potter, Robert E Schoen, Mingyang Song, Wei Sun, Amanda E Toland, Quang M Trinh, Kostas Tsilidis, Tomotaka Ugai, Caroline Y Um, Finlay A Macrae, Christophe Rosty, Thomas J Hudson, Ingrid M Winship, Amanda I Phipps, Mark A Jenkins, Ulrike Peters, Daniel D Buchanan\",\"doi\":\"10.1101/2023.03.10.23287127\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and aims: </strong>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 <i>Escherichia coli</i> harboring the <i>pks</i> island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sup>-28</sup>). 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<sup>-5</sup>) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6x10<sup>-6</sup>) 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 <i>APC</i>:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3x10<sup>-80</sup>). 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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":18659,\"journal\":{\"name\":\"medRxiv : the preprint server for health sciences\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-01-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bd/66/nihpp-2023.03.10.23287127v1.PMC10120801.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"medRxiv : the preprint server for health sciences\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2023.03.10.23287127\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv : the preprint server for health sciences","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2023.03.10.23287127","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.
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.
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