Citation: | Sumeng Wang, Silu Chen, Huiqin Li, Shuai Ben, Tingyu Zhao, Rui Zheng, Meilin Wang, Dongying Gu, Lingxiang Liu. Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS[J]. The Journal of Biomedical Research, 2024, 38(1): 37-50. DOI: 10.7555/JBR.37.20230081 |
The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis, but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking. To address this gap, we conducted a study aiming to investigate this association and identify relevant biomarkers. We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment, biological activity, and the immune microenvironment. Additionally, we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies (GWASs) involving both East Asian (7062 cases and 195745 controls) and European (24476 cases and 23073 controls) populations. We employed mediation analysis to infer the causal pathway, and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells. Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1 (FEN1) gene were significantly enriched in colorectal tumor tissues, compared with normal tissues. Moreover, a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer (odds ratio = 0.94, 95% confidence interval: 0.90–0.97, Pmeta = 4.70 × 10−9). Importantly, we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors, and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication. In conclusion, this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity, expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.
This study was partly supported by the National Natural Science Foundation of China (Grant No. 82173601) and Yili & Jiangsu Joint Institute of Health (Grant No. yl2021ms02).
We thank the participants who generously gave their help in the study. We also thank the Genetics and Epidemiology of Colorectal Cancer Consortium and Biobank Japan for providing European and East Asian colorectal cancer GWAS data.
CLC number: R735.3, Document code: A
The authors reported no conflict of interests.
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