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 po...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 FAM57A and rs526835,which could inform future precision prevention and personalized cancer therapies.展开更多
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)。
文摘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 FAM57A and rs526835,which could inform future precision prevention and personalized cancer therapies.
