Systematic functional interrogation of genome-wide association studies locus 17p13.3 deciphered role and genetic control of FAM57A in colorectal cancer development  

作　　者：Jinyu Huang Jiabin Mo Runying Xu Xiaojun Yang Yaoyao Tian Caibo Ning Shuxin Song Xu Chen Yimin Cai Ying Zhu Bin Li Chaoqun Huang Meng Jin Xiaoping Miao 

机构地区：[1]Department of Epidemiology and Biostatistics,School of Public Health,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [2]Department of Epidemiology and Biostatistics,School of Public Health,TaiKang Center for Life and Medical Sciences,Wuhan University,Wuhan 430071,China [3]Department of Gastrointestinal Surgery,Zhongnan Hospital of Wuhan University,Wuhan 430000,China [4]Department of Integrated Traditional Chinese and Western Medicine,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [5]Department of Oncology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China

出　　处：《Chinese Journal of Cancer Research》2024年第5期562-576,共15页中国癌症研究（英文版）

基　　金：supported by the Program of National Science Fund for Distinguished Young Scholars of China(No.81925032);Key Program of National Natural Science Foundation of China(No.82130098);National Natural Science Foundation of China(No.82304232)。

摘　　要：Objective: Genome-wide association studies(GWAS) have identified over 150 risk loci linked to colorectal cancer(CRC), including the 17p13.3 locus with the tag single nucleotide polymorphism(SNP) rs12603526 in the Asian population. However, the specific causal gene and the functional regulatory mechanisms in this region remain unresolved, necessitating further investigation to elucidate the underlying mechanisms of CRC.Methods: We employed an RNA interference-based functional approach to identify genes critical for CRC cell proliferation at the GWAS locus 17p13.3. Bioinformatic fine-mapping analysis was conducted to prioritize causal variants. A large-scale study involving 7,013 cases and 7,329 controls from a Chinese population, along with another cohort of 5,158 cases and 20,632 controls from the UK Biobank, was performed to validate the association between the candidate variant and the gene. A series of biological experiments was conducted to explore the function of the candidate gene and its regulatory mechanisms.Results: We identified FAM57A as a key oncogene that promotes CRC cell proliferation, and confirmed its carcinogenic role through in vitro proliferation assays. The variant rs526835 was prioritized as a causal candidate for CRC risk, located in a functional region with enhancer properties, and showed a significant quantitative association with FAM57A expression. The rs526835 [T] variant was associated with a 1.17-fold increase in CRC risk [95%confidence interval(95% CI): 1.11-1.23, P=1.23×10^(−9)] in the large-scale Chinese cohort, which was further corroborated in the UK Biobank cohort. Mechanistically, we demonstrated that rs526835 enhances a promoterenhancer interaction mediated by the transcription factor JUN, leading to increased expression of FAM57A.Conclusions: We reveal the underlying mechanisms of CRC predisposition at the GWAS locus 17p13.3.Additionally, our findings highlight the critical role of FAM57A in CRC pathogenesis and introduce a novel enhancer-promoter interaction between FAM57

关 键 词：RNA interference(RNAi) GWAS colorectal cancer(CRC) FAM57A 17p13.3 locus 

分 类 号：R735.34[医药卫生—肿瘤]