Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, 110001, China.
Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, 110001, China.
Commun Biol. 2024 Aug 31;7(1):1069. doi: 10.1038/s42003-024-06755-9.
Cellular senescence is widely acknowledged as having strong associations with cancer. However, the intricate relationships between cellular senescence-related (CSR) genes and cancer risk remain poorly explored, with insights on causality remaining elusive. In this study, Mendelian Randomization (MR) analyses were used to draw causal inferences from 866 CSR genes as exposures and summary statistics for 18 common cancers as outcomes. We focused on genetic variants affecting gene expression, DNA methylation, and protein expression quantitative trait loci (cis-eQTL, cis-mQTL, and cis-pQTL, respectively), which were strongly linked to CSR genes alterations. Variants were selected as instrumental variables (IVs) and analyzed for causality with cancer using both summary-data-based MR (SMR) and two-sample MR (TSMR) approaches. Bayesian colocalization was used to unravel potential regulatory mechanisms underpinning risk variants in cancer, and further validate the robustness of MR results. We identified five CSR genes (CNOT6, DNMT3B, MAP2K1, TBPL1, and SREBF1), 18 DNA methylation genes, and LAYN protein expression which were all causally associated with different cancer types. Beyond causality, a comprehensive analysis of gene function, pathways, and druggability values was also conducted. These findings provide a robust foundation for unravelling CSR genes molecular mechanisms and promoting clinical drug development for cancer.
细胞衰老被广泛认为与癌症密切相关。然而，细胞衰老相关（CSR）基因与癌症风险之间的复杂关系仍未得到充分探索，因果关系的见解仍难以捉摸。在这项研究中，孟德尔随机化（MR）分析用于从 866 个 CSR 基因作为暴露因素和 18 种常见癌症作为结局的汇总统计数据中得出因果推断。我们专注于影响基因表达、DNA 甲基化和蛋白质表达定量性状基因座（cis-eQTL、cis-mQTL 和 cis-pQTL）的遗传变异，这些变异与 CSR 基因的改变密切相关。选择变体作为工具变量（IV），并使用基于汇总数据的 MR（SMR）和两样本 MR（TSMR）方法分析与癌症的因果关系。贝叶斯共定位用于揭示癌症风险变异的潜在调控机制，并进一步验证 MR 结果的稳健性。我们确定了五个 CSR 基因（CNOT6、DNMT3B、MAP2K1、TBPL1 和 SREBF1）、18 个 DNA 甲基化基因和 LAYN 蛋白质表达，它们都与不同的癌症类型有因果关系。除了因果关系，我们还对基因功能、途径和药物可开发性值进行了全面分析。这些发现为揭示 CSR 基因的分子机制和促进癌症的临床药物开发提供了坚实的基础。
