A multiomic approach integrating genomic and metabolomic data highlights colorectal cancer pathways
Author(s)
Type
Journal Article
Abstract
Numerous genetic variants have been identified by genome-wide association studies as being associated with colorectal cancer (CRC) risk. Metabolome-wide association analysis was performed for 187 CRC-associated genetic variants using genomic data and untargeted 1H nuclear magnetic resonance urine metabolomics from 1951 Airwave Health Monitoring Study participants. We identified statistically significant associations between seven CRC single-nucleotide polymorphisms (SNPs) and urinary metabolites. This included SNPs within or close to RHPN2 with sucrose (P = 1.2 × 10–7), SLC6A18 with amino acids (P = 6.9 × 10–5 with tyrosine, P = 9.9 × 10–5 with leucine), and MAP2K5 and BMP2 with gut microbial metabolites (P = 1.6 × 10–4 and P = 4.4 × 10–4). The most significant correlation was followed by functional experiments in Caco-2 colon cancer cells. CRISPR-mediated knockout of a 48-nt RHPN2 intronic region containing rs10411210 in colon cancer cells compromised cell growth. RNA sequencing was performed in the two sets of clones (3 edited and 3 unedited) followed by pathway enrichment, and gene ontology analysis depicted extensive deregulation of genes (448 up- and 195 downregulated) involved in cell division and several metabolic processes. Overall, these findings demonstrate that integrating genetic and metabolomic data highlights the importance of the RHPN2 intronic locus in CRC potentially through metabolic processes affecting excretion of dietary and other metabolites.
Date Issued
2026-02-06
Date Acceptance
2026-01-13
Citation
Journal of Proteome Research, 2026, 25 (2), pp.578-588
ISSN
1535-3893
Publisher
American Chemical Society (ACS)
Start Page
578
End Page
588
Journal / Book Title
Journal of Proteome Research
Volume
25
Issue
2
Copyright Statement
© 2026 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0 .
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41603468
Subjects
GWAS
Rho GTPase
colorectal cancer
metabolomics
multiomics
urine
Humans
Colorectal Neoplasms
Polymorphism, Single Nucleotide
Metabolomics
Genome-Wide Association Study
Metabolome
Caco-2 Cells
Female
Genomics
Male
Middle Aged
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2026-01-28