Unraveling the causal nexus between serum lactate levels and cancer risk: A Mendelian randomization study

Lactate, traditionally regarded as a metabolic byproduct, has emerged as a potential signaling molecule involved in tumorigenesis. Although numerous observational studies have linked serum lactate levels to various tumors, establishing a direct causal relationship remains challenging. We conducted a 2-sample Mendelian randomization (MR) analysis using genetic instrumental variables to assess the causal effects of serum lactate levels on the risk of various cancer types. The primary analytical method used in this investigation was the random inverse-variance weighted (IVW) method, supported by auxiliary methods such as MR-Egger, weighted median, simple mode, and weighted mode, with the IVW method enabling the meta-analysis of their combined effects. To obtain exposure data, we extracted genome-wide association studies (GWAS) data on metabolite levels from the Canadian Longitudinal Study on Aging and the UK Biobank cohorts. Concurrently, GWAS data for 17 types of cancer were obtained from the IEU Open GWAS project and the GWAS Catalog project. Sensitivity analyses were performed using the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and the leave-one-out method. Our MR analysis identified a causal relationship between serum lactate and endometrial cancer (odds ratio [OR]IVW = 1.1217, 95% confidence interval [CI] = 1.0264-1.2258, P = .0112), melanoma (ORIVW = 1.0015, 95% CI = 1.0006-1.0024, P = .0010), and prostate cancer (ORIVW = 0.9578, 95% CI = 0.9319-0.9844, P = .0020). Notably, elevated lactate levels were identified as a risk factor for endometrial cancer and melanoma, while having a protective effect against prostate cancer. However, this observed relationship was not replicated in other cancer types. Our study, using GWAS data, establishes a causal link between circulating lactate and the risk of endometrial cancer, melanoma, and prostate cancer. The identification of these associations suggests the potential utility of lactate as a biomarker for these cancers or as a target for cancer prevention strategies.