Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden.
Center for Primary Health Care Research, Lund University/Region Skåne, Malmö, Sweden; Department of Family Medicine and Community Health, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, United States; Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Matsue, Japan.
EBioMedicine. 2023 Feb;88:104432. doi: 10.1016/j.ebiom.2022.104432. Epub 2023 Jan 10.
Mitochondrial dysfunction is a hallmark of cancer. However, it is unclear whether it is a cause of cancer. This two-sample Mendelian randomization (MR) analyses, uses genetic instruments to proxy the exposure of mitochondrial dysfunction and cancer summary statistics as outcomes, allowing for causal inferences.
Summary statistics from 18 common cancers (2107-491,974 participants), gene expression, DNA methylation and protein expression quantitative trait loci (eQTL, mQTL and pQTL, respectively, 1000-31,684 participants) on individuals of European ancestry, were included. Genetic variants located within or close to the 1136 mitochondrial-related genes (in cis) and robustly associated with the mitochondrial molecular alterations were used as instrumental variables, and their causal associations with cancers were examined using summary-data-based MR (SMR) analyses. An additional five MR methods were used as sensitivity analyses to confirm the casual associations. A Bayesian test for colocalization between mitochondrial molecular QTLs and cancer risk loci was performed to provide insights into the potential regulatory mechanisms of risk variants on cancers.
We identified potential causal relationships between mitochondrial-related genes and breast, prostate, gastric, lung cancer and melanoma by primary SMR analyses. The sensitivity and the colocalization analyses further refined four genes that have causal effects on three types of cancer. We found strong evidence of positive association of FDPS expression level with breast cancer risk (OR per SD, 0.66; 95% CI, 0.49-0.83; P = 9.77 × 10), NSUN4 expression level with both breast cancer risk (OR per SD, 1.05; 95% CI, 1.03-1.07; P = 5.24 × 10) and prostate cancer risk (OR per SD, 1.06; 95% CI, 1.03-1.09; P = 1.01 × 10), NSUN4 methylation level with both breast and prostate cancer risk, and VARS2 methylation level with lung cancer risk.
This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in multiple cancers. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention.
This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).
线粒体功能障碍是癌症的一个标志。然而，它是否是癌症的一个原因尚不清楚。本项两样本孟德尔随机化（MR）分析使用遗传工具来代表线粒体功能障碍的暴露和癌症的汇总统计数据作为结果，从而可以进行因果推断。
纳入了来自欧洲血统个体的 18 种常见癌症（2107-491,974 名参与者）、基因表达、DNA 甲基化和蛋白质表达定量性状基因座（eQTL、mQTL 和 pQTL，分别为 1000-31,684 名参与者）的汇总统计数据。使用位于线粒体相关基因内或附近（顺式）且与线粒体分子改变具有稳健关联的遗传变异作为工具变量，并使用基于汇总数据的 MR（SMR）分析检查它们与癌症的因果关系。另外使用了五种 MR 方法作为敏感性分析来确认因果关系。对线粒体分子 QTLs 和癌症风险位点之间的潜在调控机制进行了孟德尔随机化共定位分析。
通过主要的 SMR 分析，我们确定了线粒体相关基因与乳腺癌、前列腺癌、胃癌、肺癌和黑色素瘤之间的潜在因果关系。敏感性和共定位分析进一步细化了对三种癌症具有因果作用的四个基因。我们发现 FDPS 表达水平与乳腺癌风险之间存在强烈的正相关（SD 每增加一个标准差，OR 为 0.66；95%CI，0.49-0.83；P=9.77×10），NSUN4 表达水平与乳腺癌风险（OR 每增加一个标准差，1.05；95%CI，1.03-1.07；P=5.24×10）和前列腺癌风险（OR 每增加一个标准差，1.06；95%CI，1.03-1.09；P=1.01×10）之间存在正相关，NSUN4 甲基化水平与乳腺癌和前列腺癌风险之间存在正相关，VARS2 甲基化水平与肺癌风险之间存在正相关。
这项基于数据的 MR 研究表明，线粒体功能障碍在多种癌症中起因果作用。此外，该研究还确定了候选基因，这些基因可能成为癌症预防的潜在药物靶点。
这项工作得到了马尔默大学医院斯泰伦森基金会（20211025）的支持。
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