One‐carbon metabolite ratios as functional B‐vitamin markers and in relation to colorectal cancer risk

Abstract

One-carbon metabolism biomarkers are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs. We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk. Furthermore, the relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case-control study of 613 CRC cases and 1190 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5'-phosphate, and riboflavin. Associations with CRC risk were estimated using conditional logistic regression. We found that the ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. Additionally, associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high versus low B-vitamin status). In conclusion, ratio-based B-vitamin markers were good predictors of total B-vitamin status and displayed similar associations as total B-vitamin status with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice. This article is protected by copyright. All rights reserved.

Biomarkers of the transsulfuration pathway and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

“…In the Northern Sweden Health and Disease Study, a Bayesian network analysis of one‐carbon metabolism, including transsulfuration metabolites as well as other folate and methionine cycle metabolites, identified an independent association of circulating PLP with colorectal cancer risk, but no direct associations for homocysteine, serine, cystathionine or cysteine 27 . However, in the same cohort, a positive association was found between the ratio homocysteine:cysteine and colorectal cancer risk 28 . A 43% lower colorectal cancer risk was found in a comparison of highest to lowest fourths of cysteine concentration in the Women's Health Initiative cohort 29 .…”

Cysteine Regulates Oxidative Stress and Glutathione-Related Antioxidative Capacity before and after Colorectal Tumor Resection

“…If tumor cells capture cysteine from circulation to protect themselves against high oxidative stress, theoretically, plasma cysteine levels in CRC patients might be associated with the risk of CRC. However, no significant association between plasma cysteine levels and CRC risk has been reported in previous studies [ 21 , 22 , 23 , 24 ] except one showing that high plasma cysteine levels significantly lower the risk of rectal tumors in postmenopausal women [ 25 ]. On the other hand, we observed in our previous study that CRC patients had higher levels of plasma cysteine and GSH compared with healthy subjects [ 22 ].…”

Targeted Metabolic Profiling of Methionine Cycle Metabolites and Redox Thiol Pools in Mammalian Plasma, Cells and Urine

“…Apart from nutritional deficiencies and inherited disorders of metabolism, metabolites such as methionine and glutathione modulate T cell activation and metabolic reprogramming [13,14,15,16]. In pathology, the concentration of certain thiol and thioether metabolites has predictive value to assess mortality and morbidity in chronic disorders, such as cardiovascular disease [17,18] and cancer [19,20].…”

“…We describe a LC-MS/MS method for the simultaneous quantification of cysteine (Cys), cystine (CSSC), homocysteine (Hcy), homocystine (HSSH), reduced glutathione (GSH), oxidized glutathione (GSSG), cystathionine (Cysta), methionine (Met), and methionine sulfoxide (MSO). The non-sulfur biomarker creatinine (Crea) has recently been shown to add power to the assessment of B-vitamin status when used in combination with Hcy and Cys in human serum [18,19]. The steady state concentrations of metabolites Hcy, Cys and Crea result from the partition of Hcy via the B9- and B12-dependent Met cycle to produce SAM as well as the B6-dependent transsulfuration reactions that produce Cys.…”