Causal associations of sarcopenia-related traits with selected site-specific cancers and the mediating role of gastroesophageal reflux disease

Background: Both sarcopenia and cancers are common geriatric diseases leading to huge socioeconomic burdens. The causal impact of sarcopenia on selected site-specific cancers and the potential mediator was not clarified. Methods: Two-step, two-sample Mendelian randomization was performed to explore the causal impacts of sarcopenia on selected site-specific cancers with or without adjustment for body fat percentage (BF%), physical activity and smoking, and to evaluate proportions of the causal effects mediated by gastroesophageal reflux disease (GERD). Genetic instruments of sarcopenia-related traits, GERD, and selected site-specific cancers based on genome-wide association study were obtained from the UK Biobank, TRICL, and Japan Biobank. By searching relevant studies in PubMed, EMBASE, Cochrane Library, and Web of Science, we collected the data on the prognostic effects of sarcopenia on non-small cell lung cancer (NSCLC) for meta-analysis. Results: Lower appendicular lean mass (ALM) showed casual association with increased risks of lung adenocarcinoma, melanoma, non-melanoma skin cancer, and lymphomas. Genetically predicted lower frailty whole-body lean mass (WBLM) were associated with a higher risk of lung squamous cell carcinoma (LUSC), gastric cancer, and lymphomas. Walking pace was casually correlated with decreased risks of LUSC and cervical cancer. These causal associations were largely independent of BF%, physical activity and smoking. Further analysis showed that GERD acted as a mediator affecting the causal associations between WBLM/walking pace and LUSC, with mediation proportions of 44.23% (95% CI: 0.07–81.36%) and 86.10% (95% CI: 36.41–135.8%) for the effects of WBLM and walking pace on LUSC, respectively. Systematic review and meta-analysis demonstrated that NSCLC patients with sarcopenia had a lower overall survival (HR = 2.49, 95% CI: 2.11–2.93), progression-free survival (HR = 1.89, 95% CI: 1.10–3.24), and recurrence-free survival rates (HR = 2.03, 95% CI: 1.40–2.95). Conclusion: Our findings suggest that interventions prioritizing muscle function, especially improving walking pace, may be more effective for reducing sarcopenia-related LUSC risk than solely increasing muscle mass, with gastroesophageal reflux disease (GERD) representing a potential – but still exploratory – intervention target along this pathway.