Pre-Diagnostic Circulating Metabolites and Colorectal Cancer Risk in the Cancer Prevention Study-II Nutrition Cohort

Abstract

Untargeted metabolomic studies have identified potential biomarkers of colorectal cancer risk, but evidence is still limited and broadly inconsistent. Among 39,239 Cancer Prevention Study II Nutrition cohort participants who provided a blood sample between 1998–2001, 517 newly diagnosed colorectal cancers were identified through 30 June 2015. In this nested case–control study, controls were matched 1:1 to cases on age, sex, race and date of blood draw. Mass spectroscopy-based metabolomic analyses of pre-diagnostic plasma identified 886 named metabolites, after quality control exclusions. Conditional logistic regression models estimated multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) for 1 standard deviation (SD) increase in each metabolite with risk of colorectal cancer. Six metabolites were associated with colorectal cancer risk at a false discovery rate < 0.20. These metabolites were of several classes, including cofactors and vitamins, nucleotides, xenobiotics, lipids and amino acids. Five metabolites (guanidinoacetate, 2’-O-methylcytidine, vanillylmandelate, bilirubin (E,E) and N-palmitoylglycine) were positively associated (OR per 1 SD = 1.29 to 1.32), and one (3-methylxanthine) was inversely associated with CRC risk (OR = 0.79, 95% CI, 0.69–0.89). We did not replicate findings from two earlier prospective studies of 250 cases each after adjusting for multiple comparisons. Large pooled prospective analyses are warranted to confirm or refute these findings and to discover and replicate metabolites associated with colorectal cancer risk.

Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts

“…Nevertheless, few studies have analyzed pre-diagnostic samples to investigate whether amino acid dysregulation precedes tumorigenesis. Two other prospective case-control studies on colorectal cancer with some amino acid measurements also found no significant associations [ 19 , 31 ]. Our study is therefore the first to observe inverse associations of amino acid levels with colorectal cancer risk in a prospective setting and in independent studies.…”

“…18 Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. 19 Escuela Andaluza de Salud Pública (EASP), 18011 Granada, Spain. 20 Instituto de Investigación Biosanitaria ibs.…”

“…Despite these observations, few prospective studies have been conducted to test the hypothesis that pre-diagnostic amino acid concentrations are associated with colorectal cancer risk. Two such studies of nested case-control design that analyzed pre-diagnostic serum or plasma by untargeted metabolomics found limited dysregulation of lipophilic metabolites only [ 19 , 20 ], while in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort that measured tryptophan and serotonin levels, tryptophan was inversely associated with colon cancer [ 21 ]. The aim of the current study was thus to test these associations in a larger and more comprehensive analysis.…”

Exploring the Association between Habitual Food Intake and the Urine and Blood Metabolome in Adolescents and Young Adults: A Cohort Study

“…VMA may be associated specifically with processed and other meats due to different levels of catecholamines contained in the meats used in the production of the processed meat products. It was additionally asso-ciated with an increased risk for colorectal cancer, [47] which is known to be associated with higher consumption of processed meats. [48] Citraconate/glutaconate is an energy metabolite in the TCA cycle.…”

The underexplored links between cancer and the internal body climate: Implications for cancer prevention and treatment

“…More recently, variations in levels of glycine, serine, sphyngomyelin and free carnitine were linked to endometrial cancer development ( 75 ). Systemic circulating metabolites have also been found in other types of cancer [e.g., lung – ( 76 ); kidney – ( 77 ), ovarian-( 78 ); colorectal – ( 79 ); pancreas – ( 80 ); prostate –( 81 )] pointing to potentially novel biomarkers and treatments. Similarly, methylmalonic acid (MMA), a by-product of propionate metabolism, was found to be upregulated in the serum of older people and functions as a mediator of tumor progression ( 82 ).…”