Background.
Chronic stress may increase the risk of colorectal cancer through several biological mechanisms, including neuroendocrine activation, immune system dysregulation, and gut microbiota dysbiosis. Despite growing mechanistic evidence, only a limited number of prospective epidemiological studies have examined the relationship between chronic stress exposure and colorectal cancer incidence, yielding mixed results. Recent research has shifted toward assessing the physiological imprint of chronic stress using the allostatic load model. Allostatic load reflects the multisystem biological burden experienced as a result of repeated adaptation to stress, and is traditionally measured using an index, constructed from neuroendocrine, cardiometabolic, and immune biomarkers.
Objectives.
To investigate the association between pre-diagnostic allostatic load and the risk of developing colorectal cancer in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC).
Methods.
We conducted a case–control study nested within the EPIC–Spain cohort, which recruited 32,895 participants between 1992 and 1996 from the provinces of Granada, Murcia, Navarra, and Gipuzkoa. A total of 998 incident colorectal cancer cases (41% women; mean age at recruitment: 52 years), diagnosed through 2018, were individually matched to 998 cancer-free controls by age, sex, time since blood draw, and fasting status. To construct the allostatic load index, 16 biomarkers—cortisol, dehydroepiandrosterone sulfate, insulin-like growth factor 1, body mass index, waist-to-height ratio, insulin resistance, triglycerides, total cholesterol, HDL cholesterol, TC/HDL ratio, creatinine, albumin, C-reactive protein, interleukin-6, and immunoglobulin E—were assessed from pre-diagnostic serum samples and physical examinations. Conditional logistic regression models, adjusted for educational level, smoking status, physical activity, diet, and comorbidity, were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between the allostatic load index and colorectal cancer. Random forest classification models and weighted quantile sum (WQS) mixture models were also fitted to identify which biomarkers contribute to the discrimination between cases and controls.
Results.
On average, 16 years elapsed between recruitment and end of follow-up (case diagnosis). Higher allostatic load was associated with increased colorectal cancer risk, with an OR of 1.09 (95% CI: 1.03–1.16) per one-unit increase and an OR of 1.37 (95% CI: 1.03–1.83) for the highest versus lowest quartile. The association was observed regardless of sex or age and for colon but not rectal cancer. Random forest and WQS models showed relatively even distributions of importance values and weights across biomarkers, suggesting that cancer risk was driven by a multisystem profile of neuroendocrine, metabolic, and inflammatory dysregulation.
Conclusions/Implications for practice or policy.
Higher pre-diagnostic allostatic load was associated with an increased risk of colorectal cancer in the EPIC–Spain cohort. These findings reinforce the validity of the allostatic load index as a biologically meaningful operationalization of chronic stress in cancer research. They also highlight the potential relevance of allostatic load as a translational biomarker, bridging basic and epidemiological research on stress and cancer, and opening new approaches for risk stratification and prevention in colorectal cancer.
Funding: CIBERESP (ESP24PI03). Health Institute Carlos III (CP23/00024 & PI25/00283). AECC (ALPER-GAST).