Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
J Steroid Biochem Mol Biol. 2024 Oct;243:106584. doi: 10.1016/j.jsbmb.2024.106584. Epub 2024 Jul 13.
Female cancers, especially breast, ovarian, cervical, and endometrial cancers, constitute a major threat to women's health worldwide. In view of the complex genetic background of cancers cannot be fully explained with current genetic information, we used a bidirectional two-sample mendelian randomization approach to explore the causal associations between serum metabolites and four major female cancers-breast, ovarian, cervical, and endometrial cancers. We analyzed the metabolites dataset from the Canadian Longitudinal Study of Aging and cancer datasets from the 10th round of the Finngen project. Replication analyses was performed with Cancer Association Consortium and Leo's studies. Instrumental variables were analyzed using methods including the Wald ratio, inverse-variance weighted, MR-Egger, and weighted median. To ensure robustness, sensitivity analyses were performed using Cochrane's Q, Egger's intercept, MR-PRESSO, and leave-one-out methods. After meticulous analysis, we obtained levels of 3-hydroxyoleoylcarnitine, hexadecanedioate, tetradecanedioate, and carnitine C14 with robust causal associations with breast cancer, levels of 5alpha-androstan-3alpha,17beta-diol monosulfate (1), androstenediol (3beta,17beta) monosulfate (1), androsterone sulfate, and 5alpha-androstan-3beta,17beta-diol disulfate causal associations with endometrial cancer. The reverse analysis showed that breast, ovarian, and endometrial cancer and survival of breast and ovarian cancer were found to have causal relationships with 8, 5, 2, 6, and 3 metabolites, respectively. These insights underscore the potential roles of specific metabolites in the etiology of female cancers, providing new biomarkers for early detection, risk stratification, and disease progression monitoring. Further research could elucidate how these metabolites influence specific pathways in cancer development, offering theoretical foundations for prevention and treatment strategies.
女性癌症，尤其是乳腺癌、卵巢癌、宫颈癌和子宫内膜癌，对全球女性健康构成了重大威胁。鉴于癌症的复杂遗传背景不能仅用当前的遗传信息来充分解释，我们使用双向两样本孟德尔随机化方法来探索血清代谢物与四种主要女性癌症（乳腺癌、卵巢癌、宫颈癌和子宫内膜癌）之间的因果关联。我们分析了来自加拿大老龄化纵向研究和芬兰第十轮研究的癌症数据集的代谢物数据集。使用癌症协会联盟和 Leo 研究进行了复制分析。使用 Wald 比、逆方差加权、MR-Egger 和加权中位数等方法分析了工具变量。为了确保稳健性，使用 Cochrane's Q、Egger 的截距、MR-PRESSO 和逐一剔除方法进行了敏感性分析。经过细致的分析，我们获得了与乳腺癌具有稳健因果关联的 3-羟基油酰肉碱、十六烷二酸、十四烷二酸和肉碱 C14 的水平，以及与子宫内膜癌具有因果关联的 5alpha-雄烷-3alpha，17beta-二醇单硫酸盐（1）、雄烯二酮（3beta，17beta）单硫酸盐（1）、雄酮硫酸盐和 5alpha-雄烷-3beta，17beta-二醇二硫酸盐的水平。反向分析显示，乳腺癌、卵巢癌和子宫内膜癌以及乳腺癌和卵巢癌的生存与 8、5、2、6 和 3 种代谢物分别存在因果关系。这些发现强调了特定代谢物在女性癌症发病机制中的潜在作用，为早期检测、风险分层和疾病进展监测提供了新的生物标志物。进一步的研究可以阐明这些代谢物如何影响癌症发展中的特定途径，为预防和治疗策略提供理论基础。
