TY  - JOUR
AU  - Chen, Zhishan
AU  - Song, Wenqiang
AU  - Shu, Xiao-Ou
AU  - Wen, Wanqing
AU  - Devall, Matthew
AU  - Dampier, Christopher
AU  - Moratalla-Navarro, Ferran
AU  - Cai, Qiuyin
AU  - Long, Jirong
AU  - Van Kaer, Luc
AU  - Wu, Lan
AU  - Huyghe, Jeroen R
AU  - Thomas, Minta
AU  - Hsu, Li
AU  - Woods, Michael O
AU  - Albanes, Demetrius
AU  - Buchanan, Daniel D
AU  - Gsur, Andrea
AU  - Hoffmeister, Michael
AU  - Vodicka, Pavel
AU  - Wolk, Alicja
AU  - Marchand, Loic Le
AU  - Wu, Anna H
AU  - Phipps, Amanda I
AU  - Moreno, Victor
AU  - Ulrike, Peters
AU  - Zheng, Wei
AU  - Casey, Graham
AU  - Guo, Xingyi
TI  - Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.
JO  - Journal of the National Cancer Institute
VL  - 116
IS  - 1
SN  - 0027-8874
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2023-01729
SP  - 127-137
PY  - 2024
N1  - 2024 Jan 10;116(1):127-137
AB  - Transcriptome-wide association studies (TWAS) have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large TWAS and an alternative splicing-TWAS (sp-TWAS) in CRC using improved genetic prediction models and performed in-depth functional investigations.We analyzed RNA-sequencing (RNA-seq) 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-seq 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 three selected genes in multiple CRC cell lines.We identified a total of 57 putative CRC susceptibility genes, which included the 48 genes from TWAS and 15 genes from sp-TWAS, at Bonferroni-corrected P < 0.05. 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 two unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166.This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.
KW  - Alternative splicing (Other)
KW  - Colorectal cancer (Other)
KW  - TWAS (Other)
KW  - susceptibility genes (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37632791
DO  - DOI:10.1093/jnci/djad178
UR  - https://inrepo02.dkfz.de/record/282345
ER  -