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Abstract
Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.
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1 Shanghai Jiao Tong University, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)
2 Shanghai Ocean University, Key Laboratory of Aquacultural Resources and Utilization, Ministry of Education, College of Fishery and Life Science, Shanghai, China (GRID:grid.412514.7) (ISNI:0000 0000 9833 2433)
3 Shanghai Jiao Tong University, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); University of Michigan School of Medicine, Departments of Surgery and Pathology, Center of Excellence for Cancer Immunology and Immunotherapy, the University of Michigan Rogel Cancer Center, Graduate programs in Immunology and Cancer Biology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370)
4 Shanghai Jiao Tong University, Division of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)
5 Shanghai Jiao Tong University, Department of Pathology, Renji Hospital, School of Medicine, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)
6 University of Michigan School of Medicine, Departments of Surgery and Pathology, Center of Excellence for Cancer Immunology and Immunotherapy, the University of Michigan Rogel Cancer Center, Graduate programs in Immunology and Cancer Biology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370)