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...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,P_(meta)=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.展开更多
Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from ...Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from multiple points of view such as oncogenes,tumor suppressor genes,DNA mutations and repairs,autophagy,cancer stemness,and mitochondrial metabolism and alteration.Nowadays,not only medical data from hospitals but also public big data exist on internet websites.Consequently,the importance of computational science has vastly increased in biological and medical sciences.Using statistical or mathematical analyses of these medical data with conventional experiments,many researchers have recently shown that there is a strong relationship between the biological metabolism and chemoresistance for cancer therapy.For example,folate metabolism that mediates one-carbon metabolism and polyamine metabolism have garnered attention regarding their association with cancer.It has been suggested that these metabolisms may be involved in causing resistance to chemotherapy.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.82173601)Yili&Jiangsu Joint Institute of Health(Grant No.yl2021ms02).
文摘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,P_(meta)=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.
基金Our research group was funded by Taiho Pharmaceutical Co.,Ltd.(Tokyo,Japan),UNITECH Co.,Ltd.(Chiba,Japan),IDEA Consultants Inc.(Tokyo,Japan),Kinshu-kai Medical Corporation(Osaka,Japan).
文摘Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from multiple points of view such as oncogenes,tumor suppressor genes,DNA mutations and repairs,autophagy,cancer stemness,and mitochondrial metabolism and alteration.Nowadays,not only medical data from hospitals but also public big data exist on internet websites.Consequently,the importance of computational science has vastly increased in biological and medical sciences.Using statistical or mathematical analyses of these medical data with conventional experiments,many researchers have recently shown that there is a strong relationship between the biological metabolism and chemoresistance for cancer therapy.For example,folate metabolism that mediates one-carbon metabolism and polyamine metabolism have garnered attention regarding their association with cancer.It has been suggested that these metabolisms may be involved in causing resistance to chemotherapy.
