Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival
Authors: 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. , Trinh Quang M. , Tsilidis Kostas , Ugai Tomotaka , Um Caroline Y , Macrae Finlay A. , Rosty Christophe , Hudson Thomas J. , Winship Ingrid M. , Phipps Amanda I. , Jenkins Mark A. , Peters Ulrike , Buchanan Daniel D. 
Published: March 2023

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 ofEscherichia coliharboring thepksisland 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=1.5×10-28). 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=1×10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6×10-6) 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 theAPC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3×10-80). 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.