Integrative analyses of dicarbonyls and advanced glycation end-products with multiomic profiles across tissue, plasma and stool samples reveal methylglyoxal accumulation in colon cancer.

MGO was markedly accumulated in tumor tissue compared with adjacent normal mucosa in colon cancer patients.

• Analysis performed in matched tumor tissue and adjacent normal mucosa from 26 sporadic colon cancer patients
• Targeted tandem mass spectrometry was used to measure MGO, GO, 3-DG and major AGEs
• The accumulation of MGO in tumor tissue was a central finding of the study
• Higher levels of the MGO-derived AGE MG-H1 (Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine) also accompanied MGO accumulation in tumor tissue

Tissue MG-H1 concentrations significantly correlated with corresponding plasma MG-H1 levels.

• Correlation was observed between tumor tissue MG-H1 and plasma MG-H1 from the same individuals
• MG-H1 is the major MGO-derived advanced glycation end-product
• This finding suggests plasma MG-H1 may serve as a surrogate marker for tissue MGO-related AGE burden
• Measurements were performed in matched specimens (tumor tissue, adjacent mucosa, plasma, and stool) from the same 26 patients

Elevated tumor MGO levels were associated with up-regulation of GLO1, DDOST, and TPI, and down-regulation of CD36 in tumor RNA-sequencing data.

• GLO1 encodes the detoxifying enzyme glyoxalase-1, responsible for MGO detoxification
• DDOST codes for the AGE-clearance receptor AGE-R1
• TPI (triose phosphate isomerase) is described as a glycolytic flux marker
• CD36 is an AGE-scavenger receptor that was down-regulated in association with elevated tumor MGO
• These findings suggest a candidate remodeling of dicarbonyl-handling pathways in colon cancer tumor tissue

The MGO/GO ratio in tumors was positively associated with the relative abundances of Fusobacterium nucleatum and Parvimonas micra in stool metagenomics.

• Both Fusobacterium nucleatum and Parvimonas micra are described as bacterial species related to colorectal carcinogenesis
• Stool shotgun metagenomics was generated from the same 26 individuals
• The MGO/GO ratio in tumors was also associated with metagenomic signatures of oral-derived taxa colonizing the gut
• This represents an integrative association between tissue dicarbonyl stress and gut microbial composition

An integrative multi-specimen, multiomics analysis was performed combining dicarbonyl/AGE measurements with tumor RNA-sequencing, untargeted plasma metabolomics, and stool shotgun metagenomics.

• Study included 26 sporadic colon cancer patients
• Four specimen types were analyzed per patient: matched tumor tissue, adjacent normal mucosa, plasma, and stool
• Dicarbonyls measured included MGO, GO, and 3-DG; AGEs included MG-H1 and other major AGEs
• Targeted tandem mass spectrometry was the analytical method for dicarbonyl and AGE quantification
• The study is described as a pilot integrative analysis

Dicarbonyls and AGEs have been implicated in inflammation and carcinogenesis, but their distribution across tumor tissue and surrogate specimens and relationship to systemic metabolism and gut microbiota in colon cancer was poorly understood prior to this study.

• AGEs arise from the reaction of proteins with reactive dicarbonyl compounds such as MGO, GO, and 3-deoxyglucosone (3-DG)
• Prior to this study, how dicarbonyls and AGEs relate to AGE-related pathways and alterations in gut microbiota in colon cancer remained poorly understood
• The study addresses a gap regarding distribution across tumor tissue and surrogate specimens (plasma, stool)

The study identified novel coherent associations among tissue, circulating, and stool levels of MGO-derived AGEs, expression of AGE-related metabolic pathways, and microbial signatures in colon cancer.

• The authors describe these as 'candidate molecular and microbial interactions' that may provide novel insights into dicarbonyl stress involvement in tumor biology
• Confirmation in larger studies is noted as necessary
• The integrative approach across four specimen types and three omic platforms enabled these cross-specimen associations
• The findings are framed as hypothesis-generating given the pilot nature of the study (n=26)