Epidemiologic factors in relation to colorectal cancer risk and survival by genotoxic colibactin mutational signature.

BACKGROUND:The genotoxin colibactin causes a tumor single base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors association with colorectal cancer (CRC) risk and survival differ 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 CRC risk by SBS88 were assessed using multinomial regression (N=4,308 cases, 14,192 controls; cohort-only cases N=1,911), and with CRC-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 CRC than SBS88-negative CRC [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 BMI, alcohol, and fruit intake with CRC risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse CRC-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 CRC risk or survival. Higher BMI may be associated with worse CRC-specific survival among those SBS88-positive, however validation is needed in samples with whole-genome or exome sequencing available. IMPACT:This study highlights the importance of identification of tumor phenotypes related to CRC and understanding potential heterogeneity for risk and survival.