Mendelian randomization analysis of the causal relationships between dasatinib target genes and colorectal cancer and the mediating role of immune cells
10.7659/j.issn.1005-6947.250240
- VernacularTitle:达沙替尼药靶基因与结直肠癌因果关系及其免疫细胞中介作用的孟德尔随机化研究
- Author:
Meirong WU
1
;
Buning TIAN
;
Kai GAO
;
Jianyu ZHOU
Author Information
1. 中南大学湘雅三医院 日间手术中心,湖南 长沙 410013
- Publication Type:Journal Article
- Keywords:
Colorectal Neoplasms;
Dasatinib;
Immune Cells;
Mendelian Randomization Analysis
- From:
Chinese Journal of General Surgery
2025;34(10):2138-2147
- CountryChina
- Language:Chinese
-
Abstract:
Background and Aims:Colorectal cancer(CRC)has a complex pathogenesis,and current treatments remain limited in efficacy for advanced metastatic disease.Dasatinib is a multi-target tyrosine kinase inhibitor that has shown potential antitumor activity in various solid tumors.This study aimed to evaluate the causal relationships between dasatinib-related target genes and CRC based on genetic variation,and to explore the mediating role of immune cells,thereby providing genetic epidemiological evidence for the prevention and targeted therapy of CRC.Methods:Dasatinib-related target genes were identified through DrugBank,and the corresponding eQTLs,GWAS data for CRC(ebi-a-GCST90018808),and 731 immune-cell traits were obtained from the IEU OpenGWAS database.A two-sample Mendelian randomization(MR)framework with a two-step mediation approach was applied:first,to assess the causal relationship between dasatinib target genes(as exposures)and CRC;second,to evaluate the causal effects between target genes and immune cells,as well as between immune cells and CRC;and finally,to calculate the proportion of mediated effects.Wald ratio,inverse-variance weighted(IVW),MR-Egger,MR-PRESSO,Cochran's Q,I2,and leave-one-out analyses were used to examine heterogeneity,horizontal pleiotropy,and robustness.Results:MR results showed that dasatinib-associated inhibition of ABL1 was significantly associated with a reduced risk of CRC(OR=0.511 0,95%CI=0.323 1-0.808 0,P=0.004 1).Inhibition of YES1 was also associated with decreased CRC risk(IVW OR=0.889 9,95%CI=0.811 6-0.975 8,P=0.013 1),with no evident heterogeneity or horizontal pleiotropy among the corresponding SNPs.Further analysis revealed that dasatinib-related inhibition of YES1 significantly reduced the levels of IgD-CD24-AC level(OR=0.818 0,95%CI=0.678 2-0.986 7,P=0.035 7),and this immune cell subset itself was identified as a risk factor for CRC(OR=1.105 7,95%CI=1.029 6-1.187 5,P=0.005 7).Mediation analysis indicated that IgD-CD24-AC accounted for-9.89%and 17.31%of the mediation effects in the ABL1→CRC and YES1→CRC pathways,respectively.Conclusion:Genetic evidence from MR suggests dasatinib-target genes ABL1 and YES1 are causally linked to reduced CRC risk,with IgD-CD24-AC partially mediating the YES1-related protective effect.These findings point to immune-mediated mechanisms underlying dasatinib's potential influence on CRC risk;further experimental validation and replication across populations are warranted.
