{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T21:55:49Z","timestamp":1789682149970,"version":"4.0.1"},"posted":{"date-parts":[[2023,3,12]]},"group-title":"Oncology","reference-count":50,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Aims<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    harboring the\n                    <jats:italic>pks<\/jats:italic>\n                    island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    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=1.5\u00d710\n                    <jats:sup>-28<\/jats:sup>\n                    ). 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=1\u00d710\n                    <jats:sup>-5<\/jats:sup>\n                    ) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6\u00d710\n                    <jats:sup>-6<\/jats:sup>\n                    ) 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\n                    <jats:italic>APC<\/jats:italic>\n                    :c.835-8A&gt;G mutation (OR=65.5, 95%CI=39.0-110.0, p=3\u00d710\n                    <jats:sup>-80<\/jats:sup>\n                    ). 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.03.10.23287127","type":"posted-content","created":{"date-parts":[[2023,3,12]],"date-time":"2023-03-12T14:25:10Z","timestamp":1678631110000},"source":"Crossref","is-referenced-by-count":21,"title":["Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5096-4735","authenticated-orcid":false,"given":"Peter","family":"Georgeson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Steinfelder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabitha 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