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Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes
X. Guo, J. Ping, Y. Yang, X. Su, XO. Shu, W. Wen, Z. Chen, Y. Zhang, R. Tao, G. Jia, J. He, Q. Cai, Q. Zhang, GG. Giles, R. Pearlman, G. Rennert, P. Vodicka, A. Phipps, SB. Gruber, G. Casey, U. Peters, J. Long, W. Lin, W. Zheng
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Grantová podpora
R37 CA227130
NCI NIH HHS - United States
R01 CA235553
NCI NIH HHS - United States
R01 CA269589
NCI NIH HHS - United States
R37CA227130
National Cancer Institute (NCI)
R01 CA202981
NCI NIH HHS - United States
NLK
Free Medical Journals
od 1941 do Před 1 rokem
Freely Accessible Science Journals
od 1941 do Před 1 rokem
Open Access Digital Library
od 1941-01-01
Open Access Digital Library
od 1941-01-01
- MeSH
- 3' nepřekládaná oblast * genetika MeSH
- celogenomová asociační studie * MeSH
- genetická predispozice k nemoci * MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- lokus kvantitativního znaku MeSH
- messenger RNA genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory * genetika MeSH
- polyadenylace * MeSH
- regulace genové exprese u nádorů MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Alternative polyadenylation (APA) modulates mRNA processing in the 3'-untranslated regions (3' UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk. Genetic models were built to predict APA levels in multiple tissues using genotype and RNA sequencing data from 1,337 samples from the Genotype-Tissue Expression project. Associations of genetically predicted APA levels with cancer risk were assessed by applying the prediction models to data from large genome-wide association studies of six common cancers among European ancestry populations: breast, ovarian, prostate, colorectal, lung, and pancreatic cancers. A total of 58 risk genes (corresponding to 76 APA sites) were associated with at least one type of cancer, including 25 genes previously not linked to cancer susceptibility. Of the identified risk APAs, 97.4% and 26.3% were supported by 3'-UTR APA quantitative trait loci and colocalization analyses, respectively. Luciferase reporter assays for four selected putative regulatory 3'-UTR variants demonstrated that the risk alleles of 3'-UTR variants, rs324015 (STAT6), rs2280503 (DIP2B), rs1128450 (FBXO38), and rs145220637 (LDHA), significantly increased the posttranscriptional activities of their target genes compared with reference alleles. Furthermore, knockdown of the target genes confirmed their ability to promote proliferation and migration. Overall, this study provides insights into the role of APA in the genetic susceptibility to common cancers. Significance: Systematic evaluation of associations of alternative polyadenylation with cancer risk reveals 58 putative susceptibility genes, highlighting the contribution of genetically regulated alternative polyadenylation of 3'UTRs to genetic susceptibility to cancer.
Cancer Epidemiology Division Cancer Council Victoria Melbourne Australia
Center for Public Health Genomics University of Virginia Charlottesville Virginia
Department of Biochemistry and Molecular Biology University of Calgary Calgary Canada
Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville Tennessee
Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel
Department of Epidemiology University of Washington School of Public Health Seattle Washington
Department of Medical Genetics University of Calgary Calgary Canada
Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic
Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington
Citace poskytuje Crossref.org
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