Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature

Claire E. Thomas, Peter Georgeson, Conghui Qu, Robert S. Steinfelder, Daniel D. Buchanan, Mingyang Song, Tabitha A. Harrison, Caroline Y. Um, Meredith A. Hullar, Mark A. Jenkins, Bethany Van Guelpen, Brigid M. Lynch, Yohannes Adama Melaku, Jeroen R. Huyghe, Elom K. Aglago, Sonja I. Berndt, Lisa A. Boardman, Peter T. Campbell, Yin Cao, Andrew T. ChanDavid A. Drew, Jane C. Figueiredo, Amy J. French, Marios Giannakis, Ellen L. Goode, Stephen B. Gruber, Andrea Gsur, Marc J. Gunter, Michael Hoffmeister, Li Hsu, Wen Yi Huang, Victor Moreno, Neil Murphy, Polly A. Newcomb, Christina C. Newton, Jonathan A. Nowak, Mireia Obón-Santacana, Shuji Ogino, Wei Sun, Amanda E. Toland, Quang M. Trinh, Tomotaka Ugai, Syed H. Zaidi, Ulrike Peters, Amanda I. Phipps

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Original languageEnglish
Pages (from-to)OF1-OF13
JournalCancer Epidemiology Biomarkers and Prevention
Volume33
Issue number4
DOIs
StatePublished - 1 Apr 2024
Externally publishedYes

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