Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis:Evidenced by an integrated approach of trans-omics and GWAS
Sumeng Wang1
Silu Chen2
Huiqin Li3
Shuai Ben2
Tingyu Zhao1
Rui Zheng2
Meilin Wang2
Dongying Gu4
Lingxiang Liu1
1.Department of Oncology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China2.Department of Environmental Genomics,Jiangsu Key Laboratory of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Department of Genetic Toxicology,the Key Laboratory of Modern Toxicology of Ministry of Education,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China3.Department of Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China4.Department of Oncology,Nanjing First Hospital,Nanjing Medical University,Nanjing,Jiangsu 210006,China
摘要：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(7 062 cases and 195 745 controls)and European(24 476 cases and 23 073 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.
机标关键词：environmentintegratedgeneticmicrogwasapproachcausalcolorectal
分类号：R735.3(消化系肿瘤)
论文发表日期：2024-01-30
在线出版日期：2026-03-31（本平台首次上网日期，不代表文献的发表时间）
页数：15( 中插3,37-50 )
英文信息