Systematic investigation of genetically determined plasma and urinary metabolites to discover potential interventional targets for colorectal cancer

Jing Sun, Jianhui Zhao, Siyun Zhou, Xinxuan Li, Tengfei Li, Lijuan Wang, Shuai Yuan, Dong Chen, Philip J Law, Susanna C. Larsson, Susan M Farrington, Richard S Houlston, Malcolm G Dunlop, Evropi Theodoratou, Xue Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background
We aimed to identify plasma and urinary metabolites related to colorectal cancer (CRC) risk and elucidate their mediator role in the associations between modifiable risk factors and CRC.

Methods
Metabolite quantitative trait loci were derived from two published metabolomics genome-wide association studies (GWASs), and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (100,204 cases; 154,587 controls) and the FinnGen cohort (4,957 cases; 304,197 controls). Mendelian randomization (MR) and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable MR and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC.

Results
The study identified 30 plasma metabolites and four urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (i.e., Olipudase alfa, Tilactase). Thirteen modifiable risk factors were associated with nine metabolites and eight of these modifiable risk factors were associated with CRC risk. These nine metabolites mediated the effect of modifiable risk factors (Actinobacteria, BMI, waist-hip ratio, fasting insulin, smoking initiation) on CRC.

Conclusion
This study identified key metabolite biomarkers associated with CRC and elucidated their mediator roles in the associations between modifiable risk factors and CRC. These findings provide new insights into the etiology and potential therapeutic targets for CRC and the etiological pathways of modifiable environmental factors with CRC.
Original languageEnglish
Article numberdjae089
JournalJournal of the National Cancer Institute (JNCI)
Early online date22 Apr 2024
DOIs
Publication statusE-pub ahead of print - 22 Apr 2024

Keywords / Materials (for Non-textual outputs)

  • Colorectal cancer
  • Metabolite biomarker
  • Metabolome-wide Mendelian randomization
  • Modifiable risk factor
  • Drug target

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