Yang Lei, Zheng Yan, Li Faping, Yu Jinyu
Department of Urology, The First Hospital of Jilin University, Changchun, China.
Department of Pathology, The First Hospital of Jilin University, Changchun, China.
Medicine (Baltimore). 2025 Jul 25;104(30):e43388. doi: 10.1097/MD.0000000000043388.
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.
乳酸，传统上被视为一种代谢副产物，现已成为一种参与肿瘤发生的潜在信号分子。尽管众多观察性研究已将血清乳酸水平与各种肿瘤联系起来，但要确立直接的因果关系仍具有挑战性。我们使用基因工具变量进行了一项两样本孟德尔随机化（MR）分析，以评估血清乳酸水平对各种癌症类型风险的因果效应。本研究采用的主要分析方法是随机逆方差加权（IVW）法，并辅以MR-Egger、加权中位数、简单模式和加权模式等方法，IVW法能够对它们的综合效应进行荟萃分析。为了获取暴露数据，我们从加拿大衰老纵向研究和英国生物银行队列中提取了关于代谢物水平的全基因组关联研究（GWAS）数据。同时，从IEU开放GWAS项目和GWAS目录项目中获取了17种癌症的GWAS数据。使用 Cochr an Q检验、MR-Egger截距检验、MR-PRESSO和留一法进行敏感性分析。我们的MR分析确定血清乳酸与子宫内膜癌（比值比[OR]IVW = 1.1217，95%置信区间[CI] = 1.0264 - 1.2258，P = 0.0112）、黑色素瘤（ORIVW = 1.0015，95% CI = 1.0006 - 1.0024，P = 0.0010）和前列腺癌（ORIVW = 0.9578，95% CI = 0.9319 - 0.9844，P = 0.0020）之间存在因果关系。值得注意的是，乳酸水平升高被确定为子宫内膜癌和黑色素瘤的危险因素，而对前列腺癌具有保护作用。然而，这种观察到的关系在其他癌症类型中并未得到重复验证。我们利用GWAS数据的研究建立了循环乳酸与子宫内膜癌、黑色素瘤和前列腺癌风险之间的因果联系。这些关联的确定表明乳酸作为这些癌症的生物标志物或癌症预防策略靶点的潜在效用。
