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

doi:10.1093/jnci/djae089

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 journal › Article › peer-review

Abstract

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 2 published metabolomics genome-wide association studies, and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale genome-wide association study meta-analysis (100 204 cases, 154 587 controls) and the FinnGen cohort (4957 cases, 304 197 controls). Mendelian randomization and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable Mendelian randomization 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 4 urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, olipudase alfa, tilactase). Thirteen modifiable risk factors were associated with 9 metabolites, and 8 of these modifiable risk factors were associated with CRC risk. These 9 metabolites mediated the effect of modifiable risk factors (Actinobacteria, body mass index, waist to 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 language	English
Article number	djae089
Pages (from-to)	1303-1312
Number of pages	10
Journal	Journal of the National Cancer Institute (JNCI)
Volume	116
Issue number	8
Early online date	22 Apr 2024
DOIs	https://doi.org/10.1093/jnci/djae089
Publication status	Published - 1 Aug 2024

Keywords / Materials (for Non-textual outputs)

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

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Systematic investigation of genetically_SUN_DOA13042024_VOR_CC-BYFinal published version, 1.16 MBLicence: Creative Commons: Attribution (CC-BY)

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Colorectal cancer reduction through risk stratification of screening, follow-up and treatment
Theodoratou, E.
UK-based charities
1/05/17 → 30/04/23
Project: Research

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Sun, J., Zhao, J., Zhou, S., Li, X., Li, T., Wang, L., Yuan, S., Chen, D., Law, P. J., Larsson, S. C., Farrington, S. M., Houlston, R. S., Dunlop, M. G., Theodoratou, E., & Li, X. (2024). Systematic investigation of genetically determined plasma and urinary metabolites to discover potential interventional targets for colorectal cancer. Journal of the National Cancer Institute (JNCI), 116(8), 1303-1312. Article djae089. https://doi.org/10.1093/jnci/djae089

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

abstract = "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 2 published metabolomics genome-wide association studies, and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale genome-wide association study meta-analysis (100 204 cases, 154 587 controls) and the FinnGen cohort (4957 cases, 304 197 controls). Mendelian randomization and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable Mendelian randomization 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 4 urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, olipudase alfa, tilactase). Thirteen modifiable risk factors were associated with 9 metabolites, and 8 of these modifiable risk factors were associated with CRC risk. These 9 metabolites mediated the effect of modifiable risk factors (Actinobacteria, body mass index, waist to 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.",

keywords = "Colorectal cancer, Metabolite biomarker, Metabolome-wide Mendelian randomization, Modifiable risk factor, Drug target",

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

year = "2024",

month = aug,

day = "1",

doi = "10.1093/jnci/djae089",

language = "English",

volume = "116",

pages = "1303--1312",

journal = "Journal of the National Cancer Institute (JNCI)",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "8",

}

Sun, J, Zhao, J, Zhou, S, Li, X, Li, T, Wang, L, Yuan, S, Chen, D, Law, PJ, Larsson, SC, Farrington, SM, Houlston, RS, Dunlop, MG , Theodoratou, E & Li, X 2024, 'Systematic investigation of genetically determined plasma and urinary metabolites to discover potential interventional targets for colorectal cancer', Journal of the National Cancer Institute (JNCI), vol. 116, no. 8, djae089, pp. 1303-1312. https://doi.org/10.1093/jnci/djae089

TY - JOUR

T1 - Systematic investigation of genetically determined plasma and urinary metabolites to discover potential interventional targets for colorectal cancer

AU - Sun, Jing

AU - Zhao, Jianhui

AU - Zhou, Siyun

AU - Li, Xinxuan

AU - Li, Tengfei

AU - Wang, Lijuan

AU - Yuan, Shuai

AU - Chen, Dong

AU - Law, Philip J

AU - Larsson, Susanna C.

AU - Farrington, Susan M

AU - Houlston, Richard S

AU - Dunlop, Malcolm G

AU - Theodoratou, Evropi

AU - Li, Xue

PY - 2024/8/1

Y1 - 2024/8/1

N2 - 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 2 published metabolomics genome-wide association studies, and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale genome-wide association study meta-analysis (100 204 cases, 154 587 controls) and the FinnGen cohort (4957 cases, 304 197 controls). Mendelian randomization and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable Mendelian randomization 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 4 urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, olipudase alfa, tilactase). Thirteen modifiable risk factors were associated with 9 metabolites, and 8 of these modifiable risk factors were associated with CRC risk. These 9 metabolites mediated the effect of modifiable risk factors (Actinobacteria, body mass index, waist to 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.

AB - 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 2 published metabolomics genome-wide association studies, and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale genome-wide association study meta-analysis (100 204 cases, 154 587 controls) and the FinnGen cohort (4957 cases, 304 197 controls). Mendelian randomization and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable Mendelian randomization 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 4 urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, olipudase alfa, tilactase). Thirteen modifiable risk factors were associated with 9 metabolites, and 8 of these modifiable risk factors were associated with CRC risk. These 9 metabolites mediated the effect of modifiable risk factors (Actinobacteria, body mass index, waist to 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.

KW - Colorectal cancer

KW - Metabolite biomarker

KW - Metabolome-wide Mendelian randomization

KW - Modifiable risk factor

KW - Drug target

U2 - 10.1093/jnci/djae089

DO - 10.1093/jnci/djae089

M3 - Article

C2 - 38648753

SN - 0027-8874

VL - 116

SP - 1303

EP - 1312

JO - Journal of the National Cancer Institute (JNCI)

JF - Journal of the National Cancer Institute (JNCI)

IS - 8

M1 - djae089

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

Colorectal cancer reduction through risk stratification of screening, follow-up and treatment

Cite this