RESUMO
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.
Assuntos
Senescência Celular , Metilação de DNA , Análise da Randomização Mendeliana , Neoplasias , Locos de Características Quantitativas , Humanos , Neoplasias/genética , Senescência Celular/genética , Predisposição Genética para Doença , Teorema de BayesRESUMO
IMPORTANCE: Gastric cancer is a significant and growing health problem in China. Studies have revealed significant differences in gastric microbiota between patients with gastric cancer and non-cancerous patients, suggesting that microbiota may play a role in tumorigenesis. In this meta-analysis, existing 16S rRNA microbial data were analyzed to find combinations consisting of five genera, which had good efficacy in distinguishing gastric cancer from non-cancerous patients in multiple types of samples. These results lend support to the use of microbial markers in detecting gastric cancer. Moreover, these biomarkers are plausible candidates for further mechanistic research into the role of the microbiota in tumorigenesis.