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@ARTICLE{Chen:282345,
author = {Z. Chen and W. Song and X.-O. Shu and W. Wen and M. Devall
and C. Dampier and F. Moratalla-Navarro and Q. Cai and J.
Long and L. Van Kaer and L. Wu and J. R. Huyghe and M.
Thomas and L. Hsu and M. O. Woods and D. Albanes and D. D.
Buchanan and A. Gsur and M. Hoffmeister$^*$ and P. Vodicka
and A. Wolk and L. L. Marchand and A. H. Wu and A. I. Phipps
and V. Moreno and P. Ulrike and W. Zheng and G. Casey and X.
Guo},
title = {{N}ovel insights into genetic susceptibility for colorectal
cancer from transcriptome-wide association and functional
investigation.},
journal = {Journal of the National Cancer Institute},
volume = {116},
number = {1},
issn = {0027-8874},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {DKFZ-2023-01729},
pages = {127-137},
year = {2024},
note = {2024 Jan 10;116(1):127-137},
abstract = {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.},
keywords = {Alternative splicing (Other) / Colorectal cancer (Other) /
TWAS (Other) / susceptibility genes (Other)},
cin = {C070},
ddc = {610},
cid = {I:(DE-He78)C070-20160331},
pnm = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
pid = {G:(DE-HGF)POF4-313},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37632791},
doi = {10.1093/jnci/djad178},
url = {https://inrepo02.dkfz.de/record/282345},
}