Journal Article

DKFZ-2023-01729

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.

Chen, Z. ; Song, W. ; Shu, X.-O. ; Wen, W. ; Devall, M. ; Dampier, C. ; Moratalla-Navarro, F. ; Cai, Q. ; Long, J. ; Van Kaer, L. ; Wu, L. ; Huyghe, J. R. ; Thomas, M. ; Hsu, L. ; Woods, M. O. ; Albanes, D. ; Buchanan, D. D. ; Gsur, A. ; Hoffmeister, M.DKFZ* ; Vodicka, P. ; Wolk, A. ; Marchand, L. L. ; Wu, A. H. ; Phipps, A. I. ; Moreno, V. ; Ulrike, P. ; Zheng, W. ; Casey, G. ; Guo, X.

2024
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/jnci/djad178

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.

Keyword(s): Alternative splicing ; Colorectal cancer ; TWAS ; susceptibility genes

Note: 2024 Jan 10;116(1):127-137

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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