Metabolomic Differences in Young-onset vs Average-onset Colorectal Adenocarcinoma

Dr. Suneel Kamath - Discover the metabolomic differences between young-onset and average-onset colorectal adenocarcinoma (CRC) through a comprehensive study. Explore the impact of genetic and environmental factors on CRC development and potential therapeutic implications.


Dr. Suneel Kamath from the Cleveland Clinic - Young onset colorectal cancer (yoCRC) has been increasing over the past few decades, and the reasons behind this rise are still not well understood. Dr. Suneel Kamath and his team conducted a study using metabolomics to gain insights into the underlying factors contributing to yoCRC. Metabolomics is a field that examines the breakdown products of the body's metabolism, including genetic and environmental influences.


The study involved patients from two biobanks at Cleveland Clinic. One biobank consisted of patients with early-stage colorectal cancer, while the other included patients with colorectal liver metastases. Healthy controls were also included, sourced from patients who had undergone liver resections for non-cancerous reasons or were liver transplant donors.


The researchers used an untargeted plasma-based GC-TOF mass spectrometry test to analyze the metabolites in the participants. They focused on amino acids, carbohydrates, and breakdown products of fatty acid metabolism. They found that citrate was significantly more abundant in average onset colorectal cancer compared to yoCRC. Additionally, several pathways related to arginine biosynthesis and various cycles showed up-regulation in average onset disease.


One of the notable findings was the activation of the arginine biosynthesis pathway in yoCRC. This pathway has connections to dietary factors such as red meat intake, which is already known to be associated with colorectal cancer. Targeting this pathway could potentially lead to therapeutic interventions for yoCRC.


Comparing young and old controls, the study revealed no significant differences in metabolites, ruling out age as the sole factor contributing to the observed differences in patients with cancer. The researchers also identified an association between higher levels of 4-hydroxyhippuric acid, a metabolite derived from plant-based sources, and better survival outcomes.


While adipic acid initially showed an association with aoCRC survival, this association disappeared after adjusting for other factors. On the other hand, the correlation between 4-hydroxyhippuric acid and survival remained strong across the entire CRC population.


Regarding yoCRC, the study found higher levels of cholesterol, which was unexpected considering these patients typically have lower rates of hyperlipidemia. However, adjusting for factors such as obesity revealed that the relationship between cholesterol and yoCRC might be confounded by these comorbidities.


In conclusion, the study highlights significant dysregulation in arginine biosynthesis and carbohydrate metabolism pathways in yoCRC. These findings underscore the importance of dietary factors such as sugar-sweetened beverages and red meat consumption in yoCRC development. The study also suggests the potential for targeting the arginine biosynthesis pathway in future treatments. Further research is needed to explore drug options that inhibit or target this pathway to improve outcomes for yoCRC patients.