PUBLICATION
Genome-wide association analyses identify CATSPERE as a mediator of colorectal cancer susceptibility and progression
- Authors
- Meng, Y., Du, M., Gu, D., Li, C., Li, S., Zhang, Q., Ben, S., Zhu, Q., Xin, J., Zhang, Z., Hu, Z., Shen, H., Jiang, K., Wang, M.
- ID
- ZDB-PUB-220126-43
- Date
- 2022
- Source
- Cancer research 82(6): 986-997 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Carcinogenesis
- Case-Control Studies
- Colorectal Neoplasms*/genetics
- Genetic Predisposition to Disease
- Genome-Wide Association Study*
- Humans
- Polymorphism, Single Nucleotide
- Zebrafish/genetics
- PubMed
- 35074755 Full text @ Cancer Res.
Citation
Meng, Y., Du, M., Gu, D., Li, C., Li, S., Zhang, Q., Ben, S., Zhu, Q., Xin, J., Zhang, Z., Hu, Z., Shen, H., Jiang, K., Wang, M. (2022) Genome-wide association analyses identify CATSPERE as a mediator of colorectal cancer susceptibility and progression. Cancer research. 82(6):986-997.
Abstract
Genome-wide association studies (GWASs) have revealed numerous genetic loci associated with colorectal cancer risk, but the mechanisms underlying these loci have not been comprehensively elucidated. In this study, we performed a GWAS meta-analysis with a two-stage replication strategy by combining eight colorectal cancer cohorts encompassing 7,186 cases and 8,512 controls in Chinese populations, accompanied by an evaluation encompassing 29,832 cases and 406,694 controls in European populations. The genetic variant rs505706 A>G, located at chr1q44 in the upstream region of catsper channel auxiliary subunit epsilon (CATSPERE), was associated with colorectal cancer risk and exhibited genome-wide significance [odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.67-0.80, P = 9.75×10-12]. Cell line and animal models were applied to assess the biological function of the genetic risk variant and the corresponding susceptibility gene. Genetically, the G allele of rs505706 resulted in long-range regulatory effects, reducing the binding affinity of POU2F1 for the CATSPERE promoter and thus abolishing the inhibitory effect of POU2F1 on CATSPERE transcription. Phenotypically, CATSPERE upregulation attenuated tumor growth in both colorectal cancer cells and xenograft models. Mechanistically, CATSPERE promoted calcium ion influx and apoptotic pathway activity. In zebrafish models, CATSPERE exerted pleiotropic effects, enhancing the progression of colorectal cancer. Collectively, these findings highlight a colorectal cancer susceptibility locus which acts to remotely modulate the activity of CATSPERE, a gene that mediates multiple functions involved in colorectal tumorigenesis and progression.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping