Metabolites, Healthy Lifestyle, and Polygenic Risk Score Associated with Upper Gastrointestinal Cancer: Findings from the UK Biobank Study.

Previous metabolomics studies have highlighted the predictive value of metabolites on upper gastrointestinal (UGI) cancer, while most of them ignored the potential effects of lifestyle and genetic risk on plasma metabolites. This study aimed to evaluate the role of lifestyle and genetic risk in the metabolic mechanism of UGI cancer. Differential metabolites of UGI cancer were identified using partial least-squares discriminant analysis and the Wilcoxon test. Then, we calculated the healthy lifestyle index (HLI) score and polygenic risk score (PRS) and divided them into three groups, respectively. A total of 15 metabolites were identified as UGI-cancer-related differential metabolites. The metabolite model (AUC = 0.699) exhibited superior discrimination ability compared to those of the HLI model (AUC = 0.615) and the PRS model (AUC = 0.593). Moreover, subgroup analysis revealed that the metabolite model showed higher discrimination ability for individuals with unhealthy lifestyles compared to that with healthy individuals (AUC = 0.783 vs 0.684). Furthermore, in the genetic risk subgroup analysis, individuals with a genetic predisposition to UGI cancer exhibited the best discriminative performance in the metabolite model (AUC = 0.770). These findings demonstrated the clinical significance of metabolic biomarkers in UGI cancer discrimination, especially in individuals with unhealthy lifestyles and a high genetic risk.

Untargeted serum metabolomics reveals potential biomarkers and metabolic pathways associated with the progression of gastroesophageal cancer.

BACKGROUND: Previous metabolic studies in upper digestive cancer have mostly been limited to cross-sectional study designs, which hinders the ability to effectively predict outcomes in the early stage of cancer. This study aims to identify key metabolites and metabolic pathways associated with the multistage progression of epithelial cancer and to explore their predictive value for gastroesophageal cancer (GEC) formation and for the early screening of esophageal squamous cell carcinoma (ESCC). METHODS: A case-cohort study within the 7-year prospective Esophageal Cancer Screening Cohort of Shandong Province included 77 GEC cases and 77 sub-cohort individuals. Untargeted metabolic analysis was performed in serum samples. Metabolites, with FDR q value < 0.05 and variable importance in projection (VIP) > 1, were selected as differential metabolites to predict GEC formation using Random Forest (RF) models. Subsequently, we evaluated the predictive performance of these differential metabolites for the early screening of ESCC. RESULTS: We found a distinct metabolic profile alteration in GEC cases compared to the sub-cohort, and identified eight differential metabolites. Pathway analyses showed dysregulation in D-glutamine and D-glutamate metabolism, nitrogen metabolism, primary bile acid biosynthesis, and steroid hormone biosynthesis in GEC patients. A panel of eight differential metabolites showed good predictive performance for GEC formation, with an area under the receiver operating characteristic curve (AUC) of 0.893 (95% CI = 0.816-0.951). Furthermore, four of the GEC pathological progression-related metabolites were validated in the early screening of ESCC, with an AUC of 0.761 (95% CI = 0.716-0.805). CONCLUSIONS: These findings indicated a panel of metabolites might be an alternative approach to predict GEC formation, and therefore have the potential to mitigate the risk of cancer progression at the early stage of GEC.

Prognostic model construction and immune microenvironment analysis of esophageal cancer based on gene expression data and microRNA target genes.

Background: Accumulating evidence suggests that microRNA-target genes are closely related to tumorigenesis and progression. This study aims to screen the intersection of differentially expressed mRNAs (DEmRNAs) and the target genes of differentially expressed microRNAs (DEmiRNAs), and to construct a prognostic gene model of esophageal cancer (EC). Methods: Gene expression, microRNA expression, somatic mutation, and clinical information data of EC from The Cancer Genome Atlas (TCGA) database were used. The intersection of DEmRNAs and the target genes of DEmiRNAs predicted by the Targetscan database and microRNA Data Integration Portal (mirDIP) database were screened. The screened genes were used to construct a prognostic model of EC. Then, the molecular and immune signatures of these genes were explored. Finally, the GSE53625 dataset from the Gene Expression Omnibus (GEO) database was further used as a validation cohort to confirm the prognostic value of the genes. Results: Six genes on the grounds of the intersection of DEmiRNAs target genes and DEmRNAs were identified as prognostic genes, including ARHGAP11A, H1.4, HMGB3, LRIG1, PRR11, and COL4A1. Based on the median risk score calculated for these genes, EC patients were divided into a high-risk group (n=72) and a low-risk group (n=72). Survival analysis showed that the high-risk group had a significantly shorter survival time than the low-risk group (TCGA and GEO, P<0.001). The nomogram evaluation showed high reliability in predicting the 1-year, 2-year, and 3-year survival probability of EC patients. Compared to low-risk group, higher expression level of M2 macrophages was found in high-risk group of EC patient (P<0.05), while STAT3 checkpoints showed attenuated expression level in high-risk group. Conclusions: A panel of differential genes was identified as potential EC prognostic biomarkers and showed great clinical significance in EC prognosis.