Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status

Abstract

Objective: To test hypotheses that appendectomy history might lower long-term colorectal cancer risk and that the risk reduction might be strong for tumors enriched with Fusobacterium nucleatum , bacterial species implicated in colorectal carcinogenesis.

Background: The absence of the appendix, an immune system organ and a possible reservoir of certain pathogenic microbes, may affect the intestinal microbiome, thereby altering long-term colorectal cancer risk.

Methods: Utilizing databases of prospective cohort studies, namely the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of appendectomy history with colorectal cancer incidence overall and subclassified by the amount of tumor tissue Fusobacterium nucleatum​​ ( Fusobacterium animalis ). We used an inverse probability weighted multivariable-adjusted duplication-method Cox proportional hazards regression model.

Results: During the follow-up of 139,406 participants (2,894,060 person-years), we documented 2811 incident colorectal cancer cases, of which 1065 cases provided tissue Fusobacterium nucleatum analysis data. The multivariable-adjusted hazard ratio of appendectomy for overall colorectal cancer incidence was 0.92 (95% CI, 0.84-1.01). Appendectomy was associated with lower Fusobacterium nucleatum -positive cancer incidence (multivariable-adjusted hazard ratio, 0.53; 95% CI, 0.33-0.85; P =0.0079), but not Fusobacterium nucleatum -negative cancer incidence (multivariable-adjusted hazard ratio, 0.98; 95% CI, 0.83-1.14), suggesting a differential association by Fusobacterium nucleatum status ( Pheterogeneity =0.015). This differential association appeared to persist in various participant/patient strata including tumor location and microsatellite instability status.

Conclusions: Appendectomy likely lowers the future long-term incidence of Fusobacterium nucleatum -positive (but not Fusobacterium nucleatum -negative) colorectal cancer. Our findings do not support the existing hypothesis that appendectomy may increase colorectal cancer risk.

Keywords: colorectal neoplasms; microbiota; molecular pathological epidemiology; prevention; risk factor.