Gene-Metabolite Interaction in the One Carbon Metabolism Pathway: Predictors of Colorectal Cancer in Multi-Ethnic Families

Abstract

For personalized healthcare, the purpose of this study was to examine the key genes and metabolites in the one-carbon metabolism (OCM) pathway and their interactions as predictors of colorectal cancer (CRC) in multi-ethnic families. In this proof-of-concept study, we included a total of 30 participants, 15 CRC cases and 15 matched family/friends representing major ethnic groups in southern California. Analytics based on supervised machine learning were applied, with the target variable being specified as cancer, including the ensemble method and generalized regression (GR) prediction. Elastic Net with Akaike’s Information Criterion with correction (AICc) and Leave-One-Out cross validation GR methods were used to validate the results for enhanced optimality, prediction, and reproducibility. The results revealed that despite some family members sharing genetic heritage, the CRC group had greater combined gene polymorphism-mutations than the family controls (p < 0.1) for five genes including MTHFR C677T, MTHFR A1298C, MTR A2756G, MTRR A66G, and DHFR 19bp. Blood metabolites including homocysteine (7 µmol/L), methyl-folate (40 nmol/L) with total gene mutations (≥4); age (51 years) and vegetable intake (2 cups), and interactions of gene mutations and methylmalonic acid (MMA) (400 nmol/L) were significant predictors (all p < 0.0001) using the AICc. The results were validated by a 3% misclassification rate, AICc of 26, and >99% area under the receiver operating characteristic curve. These results point to the important roles of blood metabolites as potential markers in the prevention of CRC. Future intervention studies can be designed to target the ways to mitigate the enzyme-metabolite deficiencies in the OCM pathway to prevent cancer.

Multiplexed nanomaterial-assisted laser desorption/ionization for pan-cancer diagnosis and classification

“…S8-S23), namely 2-oxovaleric acid, histamine, glucose, 5-hydroxymethyluracil, 2-Furoic acid, methylmalonic acid, 4-methylcatechol and L-carnitine. Most of these metabolites were reported elsewhere for the link of cancer events [46][47][48][49][50][51][52] . Importantly, amongst all 120 m/z features, these 8 metabolites correspond up to ~30 signals from Fig.…”

Construction and Analysis of Human Diseases and Metabolites Network

“…The disease node with the greatest degree (degree = 762) was that of CRC, a major cause of morbidity and mortality worldwide. The feces of CRC patients show high levels of branched chain fatty acid (BCFA), isovalerate, isobutyrate, valerate, and phenylacetate, and low levels of amino acids, sugar, methanol, and bile acids (deoxycholate, stone deoxycholate, and cholate) (Le Gall et al, 2018;Shiao et al, 2018), indicating that dysregulated metabolites can increase the risk of intestinal cancer in humans. In addition, the degree of L-Lactic acid was the largest (degree = 66; Figure 2D) among the metabolite nodes, and thus likely dysregulated in multiple diseases.…”