Colorectal cancer risk in cystic fibrosis: Systemic review and quantitative synthesis of epidemiologic, genetic, and clinical evidence.

Abstract

e15639 Background: Increased survival rates in individuals with cystic fibrosis (CF) have revealed multiple long-term complications. Recent data suggests a substantially increased risk of these individuals developing colorectal cancer (CRC), potentially associated with CFTR dysfunction, altered intestinal mucus, chronic inflammation, or microbiome-mediated genotoxicity. We conducted a systematic review and quantitative synthesis to characterize CRC risk in CF and related CFTR-associated susceptibility. Methods: PubMed, Embase, and Google Scholar were searched for eligible studies evaluating CRC risk in CF patients. Population-based studies reporting standardized incidence ratios comparing CF patients to the generalized population were included for quantitative synthesis. Long-term follow up data was summarized narratively and categorized. Additionally, cohort, hospitalization, and single-center studies describing age of onset, clinical phenotype, and temporal trends were included in the narrative analysis. Genetic association studies evaluating CRC risk among heterozygous CFTR variant carriers were reviewed. Results: Two population based studies from England and France reported CRC-specific SIRs of 5.0 (95% CI 3.2-6.9) and 4.41 (95% CI 1.62-9.59) respectively, demonstrating markedly increased risk of CRC in CF patients. Long-term follow-up data from a study conducted in the US supports this association with reported SIRs of 7.4 (95% CI 3.7-13.2) at 10 years and 6.2 (95% CI 4.2-9.0) at 20 years among non-transplant CF patients. Additionally, across registry and cohort studies, CRC has occurred at younger age in CF patients, and there is increased prevalence of precancerous lesions identified via colonoscopy. Hospitalization based analyses show increased CRC over time in CF population with higher risk of CRC-related hospitalization compared to control group. Genetic association analyses demonstrated that heterozygous carriers of pathogenic CFTR variants exhibited modest, yet statistically significant increase in risk of CRC, with odds ratios ranging from 1.11 to 1.33, suggesting CFTR-related susceptibility. Mechanistic studies implicate that CF-associated mucus dysfunction and increased vulnerability to colibactin-mediated DNA damage may be an underlying cause of colorectal carcinogenesis. Conclusions: Overall, multiple lines of evidence demonstrate a substantially increased risk of CRC in CF patients. Complementary genetic, clinical, and mechanistic data support the possibility that CFTR plays a central role in susceptibility to CRC. These findings reinforce current recommendations for earlier CRC screenings and continued surveillance in CF patients and emphasize the need for prospective population-based studies as life expectancy among CF patients continue to improve.