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Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation
Z. Chen, W. Song, XO. Shu, W. Wen, M. Devall, C. Dampier, F. Moratalla-Navarro, Q. Cai, J. Long, L. Van Kaer, L. Wu, JR. Huyghe, M. Thomas, L. Hsu, MO. Woods, D. Albanes, DD. Buchanan, A. Gsur, M. Hoffmeister, P. Vodicka, A. Wolk, LL. Marchand,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
P30 DK058404
NIDDK NIH HHS - United States
R37 CA227130
NCI NIH HHS - United States
R37 CA227130
NIH HHS - United States
NLK
Free Medical Journals
od 1996 do Před 1 rokem
Open Access Digital Library
od 1996-01-01
PubMed
37632791
DOI
10.1093/jnci/djad178
Knihovny.cz E-zdroje
- MeSH
- celogenomová asociační studie MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory * genetika MeSH
- lidé MeSH
- represorové proteiny genetika MeSH
- RNA MeSH
- transkriptom * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations. METHODS: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines. RESULTS: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166. CONCLUSION: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.
Center for Cancer Research Medical University of Vienna Vienna Austria
Consortium for Biomedical Research in Epidemiology and Public Health Madrid Spain
Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville TN USA
Department of Biostatistics University of Washington Seattle WA USA
Department of Epidemiology University of Washington Seattle WA USA
Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic
Genetic Medicine and Family Cancer Clinic The Royal Melbourne Hospital Parkville VIC Australia
Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
Memorial University of Newfoundland Discipline of Genetics St John's ON Canada
Preventative Medicine University of Southern California Los Angeles CA USA
Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA
Citace poskytuje Crossref.org
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