Abstract
Colorectal cancer (CRC) is a major public health burden and one of the leading causes of cancer-related deaths worldwide. Screening programs facilitate early diagnosis and can help to reduce poor outcomes. Serum metabolomics can extract vital molecular information that may increase the sensitivity and specificity of colonoscopy in combination with histopathological examination. The present study identifies serum metabolite patterns of treatment-naïve patients, diagnosed with either advanced adenoma (AA) or CRC in colonoscopy screenings, in the framework of the SAKKOPI (Salzburg Colon Cancer Prevention Initiative) program. We used a targeted flow injection analysis and liquid chromatography-tandem mass spectrometry metabolomics approach (FIA- and LC-MS/MS) to characterise the serum metabolomes of an initial screening cohort and two validation cohorts (in total 66 CRC, 76 AA and 93 controls). The lipidome was significantly perturbed, with a proportion of lipid species being downregulated in CRC patients, as compared to AA and controls. The predominant alterations observed were in the levels of lyso-lipids, glycerophosphocholines and acylcarnitines, but additionally, variations in the quantity of hydroxylated sphingolipids could be detected. Changed amino acid metabolism was restricted mainly to metabolites of the arginine/dimethylarginine/NO synthase pathway. The identified metabolic divergences observed in CRC set the foundation for mechanistic studies to characterise biochemical pathways that become deregulated during progression through the adenoma to carcinoma sequence and highlight the key importance of lipid metabolites. Biomarkers related to these pathways could improve the sensitivity and specificity of diagnosis, as well as the monitoring of therapies.
Highlights
Colorectal cancer (CRC) is among the three most common forms of malignancy, according to the WHO, and a leading cause of cancer-related deaths on a global level
All groups were similar in sex distribution and BMI, but the control group was younger than both the adenoma and carcinoma group
Liver parameters aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT) and concentrations of serum triglycerides were similar between all groups
Summary
Colorectal cancer (CRC) is among the three most common forms of malignancy, according to the WHO, and a leading cause of cancer-related deaths on a global level. Despite prevention programs and advancements in therapy, CRC is still the second most common cause of cancer death in Europe, accounting for 12.4% of deaths in 2020 [1,2]. This study included participants of the SAKKOPI (Salzburg Colon Cancer Prevention Initiative) program [5], who underwent CRC colonoscopy, according to national screening recommendations. Serum metabolomes from participants with diagnosed advanced adenoma (AA) or CRC, as well as from participants without AA or CRC were analysed, providing the rare opportunity to describe the metabolic status in treatment-naïve individuals. Such information is relevant to strengthen the understanding of disease-associated molecular changes and the development of diagnostic markers
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