IARC 60th Anniversary - 19-21 May 2026
Session : 19/05/26 - Posters
Genetically predicted interleukin-6 and tumor necrosis factor pathways and colorectal cancer-specific mortality
BOUKA M. 1,2, NIMPTSCH K. 1, PHAM T. 1, BOURAS E. 3, KANELLOPOULOU A. 4, PHIPPS A. 5,6, VAN GUELPEN B. 7,8, BRENNER H. 9,10,11, LI L. 12, LE MARCHAND L. 15, TSILIDIS K. 3,4, PISCHON T. 1,13,14
1 Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Molecular Epidemiology Research Group, Berlin, Germany; 2 Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Public Health, Berlin, Germany; 3 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; 4 Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; 5 Public Health Sciences Division, Fred Hutchinson Cancer Center, Washington, United States; 6 Department of Epidemiology, University of Washington, Washington, United States; 7 Department of Diagnostics and Intervention, Oncology Unit, Umeå University, Umeå, Sweden; 8 Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden; 9 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; 10 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; 11 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; 12 Department of Family Medicine, University of Virginia, Charlottesville, United States; 13 Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biobank Technology Platform, Berlin, Germany; 14 Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin,, Berlin, Germany; 15 University of Hawaii Cancer Center, Honolulu, United States
Background: Despite significant progress in identifying risk factors for colorectal cancer (CRC), factors influencing survival in people with CRC remain less understood. Pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), have been implicated in cancer progression and may influence CRC outcomes.
Objective: To investigate associations between genetically predicted levels of IL-6 and TNF-α signaling pathways and mortality in people with CRC.
Methods: We conducted a two-sample Mendelian randomization (MR) analysis using cis-acting single nucleotide polymorphisms (SNPs) associated with soluble IL-6 receptor alpha (sIL6-RA) and IL-6 signal transducer gp130 (IL6ST), representing IL-6 signaling, and with TNF-α, and its soluble receptors (sTNF-R1, sTNF-R2). SNPs were obtained separately from two large genome-wide association studies (GWAS): deCODE and UK Biobank (UKB). The outcome was CRC-specific mortality among 16,964 CRC cases (4,010 deaths) in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Analyses were stratified by tumor site and stage. The Inverse Variance Weighted (IVW) method, incorporating a correlation matrix for dependent SNPs, was used for primary analyses. Because literature links TNF-α to CRC incidence, we additionally performed a simulation study to evaluate the potential impact of collider bias resulting from restricting analyses to CRC cases.
Results: Genetically predicted sIL6-RA was weakly positively associated with CRC-specific mortality (deCODE-SNPs (n=13) HR per 1 SD increase: 1.06; 95% CI: 1.00–1.12; UKB-SNPs (n=11) HR: 1.09; 95% CI: 1.02–1.17). Genetically proxied IL6ST levels showed no association with CRC-specific mortality in the overall sample (deCODE-SNPs (n=19) HR: 1.04; 95% CI: 0.90–1.21; UKB-SNPs (n=9) HR: 1.11; 95% CI: 0.87–2.42), while higher IL6ST levels were associated with increased mortality among patients with stage 2/3 disease (deCODE-SNPs (n=19) HR: 1.45; 95% CI: 1.10–1.91; UKB-SNPs (n=9) HR: 1.87; 95% CI: 1.22–2.89). No associations were observed for TNF-α, sTNF-R1, or sTNF-R2. Findings for all exposures were consistent across both GWAS datasets. Simulation analyses for TNF-α indicated collider bias was present but limited in magnitude.
Conclusions/Implications for practise or policy: Our findings suggest that IL-6 signaling may play a role in CRC progression although of limited magnitude, whereas TNF-related pathways appear less relevant for prognosis.These findings offer insight into how two major inflammatory cytokine pathways may relate to CRC progression and help refine future efforts to identify factors related to prognosis.