Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378041%3A_____%2F24%3A00580791" target="_blank" >RIV/68378041:_____/24:00580791 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/24:10473900 RIV/00216208:11140/24:10473900

Výsledek na webu

<a href="https://academic.oup.com/jnci/article/116/1/127/7252238?login=true" target="_blank" >https://academic.oup.com/jnci/article/116/1/127/7252238?login=true</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/jnci/djad178" target="_blank" >10.1093/jnci/djad178</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation

Popis výsledku v původním jazyce

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 invitro 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.

Název v anglickém jazyce

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation

Popis výsledku anglicky

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 invitro 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JNCI-Journal of the National Cancer Institute

ISSN

0027-8874

e-ISSN

1460-2105

Svazek periodika

116

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

127-137

Kód UT WoS článku

001072729300001

EID výsledku v databázi Scopus

2-s2.0-85182091185