首页|Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks

Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks

扫码查看
原文链接
  • 万方数据
  • 维普
Genome-wide association studies(GWASs)have identified over 140 colorectal cancer(CRC)-associated loci;however,target genes at the majority of loci and underlying molecular mechanisms are poorly understood.Here,we utilized a Bayesian approach,integrative risk gene selector(iRIGS),to prioritize risk genes at CRC GWAS loci by integrating multi-omics data.As a result,a total of 105 high-confidence risk genes(HRGs)were identified,which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC.Among the 105 HRGs,CEBPB,located at the 20q13.13 locus,acted as a transcription factor playing critical roles in cancer.Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK,PI3K-Akt,and Ras signaling.Next,by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls,we elucidated that rs1810503,a putative functional variant regulating CEBPB,was associated with CRC risk(OR=0.90,95％CI=0.86-0.93,P=1.07×10-7).The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls.Mechanistically,the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via long-range promoter-enhancer interactions,mediated by the transcription factor,REST,and thus decreased CRC risk,In summary,our study provides a genetic resource and a generalizable strategy for CRC etiology investigation,and highlights the biological implications of CEBPB in CRC tumorigenesis,shedding new light on the etiology of CRC.

susceptibility genesgene screening modelsmulti-omicsGWASCEBPBlong-range promoter-enhancer interactions

Ming Zhang、Xiaoyang Wang、Nan Yang、Xu Zhu、Zequn Lu、Yimin Cai、Bin Li、Ying Zhu、Xiangpan Li、Yongchang Wei、Shaokai Zhang、Jianbo Tian、Xiaoping Miao

展开 >

Department of Epidemiology and Biostatistics,School of Public Health

Department of Gastrointestinal Oncology,Zhongnan Hospital of Wuhan University

Department of Radiation Oncology,Renmin Hospital of Wuhan University,TaiKang Center for Life and Medical Sciences,Wuhan University,Wuhan 430071,China

Research Center of Public Health,Renmin hospital of Wuhan University,Wuhan University,Wuhan 430060,China

Department of Cancer Epidemiology,The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital,Henan Engineering Research Center of Cancer Prevention and Control,Henan International Joint Laborator

Department of Gastrointestinal Surgery,Renmin Hospital of Wuhan University,Wuhan 430060,China

Department of Radiation Oncology,Renmin Hospital of Wuhan University,Wuhan 430060,China

Department of Gastrointestinal Oncology,Hubei Cancer Clinical Study Center,Zhongnan Hospital of Wuhan University,Wuhan 430062,China

Department of Cancer Epidemiology,The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital,Henan Engineering Research Center of Cancer Prevention and Control,Henan International Joint Laboratory of Cancer Prevention,Zhengzhou 450008,China

Department of Epidemiology and Biostatistics,School of Public Health,Tongji Medical College,Huazhong Universit

展开 >

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaYoung Elite Scientists Sponsorship Program by CASTFundamental Research Funds for the Central UniversitiesKnowledge Innovation Program of WuhanTranslational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan UniversityDistinguished Young Scholars of ChinaKey Program of National Natural Science Foundation of ChinaLeading Talent Program of the Health Commission of Hubei ProvinceNatural Science Foundation of Hubei ProvinceFundamental Research Funds for the Central UniversitiesFundamental Research Funds for the Central UniversitiesNational Natural Science Foundation of China

82103929822737132022QNRC0012042022kf1205whkxjsj011ZNJC20220781925032821300982019CFA0092042022rc00262042023kf100582204128

2024

10.1007/s11427-023-2439-7

中国科学:生命科学(英文版)
中国科学院

中国科学:生命科学(英文版)

CSTPCD
影响因子：0.806
ISSN：1674-7305
年,卷(期)：2024.67(1)
  • 79