Development Of A Risk Stratification Model For Prognostic Prediction Based On Glutathione Etabolism Related Enzymes In Thyroid Cancer

Background:Glutathione(GSH),the most abundant antioxidant,acts as a free radical scavenger and detoxifying agent in cells.Compared with normal cells,cancerous cells show higher levels of reactive oxygen species(ROS)to match their enhanced cell metabolism and malignant proliferation.Elevation of GSH metabolism prevent tumor from damage of oxidant.Programmed cell death,including apoptosis,autophagy,necrotizing diseases and hypertrophy,is triggered by a series of intracellular processes.Related studies have shown that GSH metabolism can even promote tumor progression by regulating various forms of programmed cell death.However,the clinical value of GSH metabolism in thyroid cancer(THCA)remained largely unknown.Methods:Collecting THCA from The Cancer Genome Atlas(TCGA)database,we systematically analyzed molecular characteristics of 24 GSH metabolism-related enzymes.Subgroups with distinct metabolic status were identified via unsupervised hierarchical clustering.To quantity the GSH metabolism status and stratify THCA patients,a 9-gene based signature was developed using LASSO-penalized Cox regression model.Results:Based on a large cohort containing 510 THCA patients from TCGA,we found that GSH metabolism related enzymes were upregulated in tumor samples and negatively correlated with disease free survival(DFS).Two subgroups with distinct metabolic status and survival outcomes were identified based on expression of GSH metabolism related enzymes.To expand the application of GSH metabolism related enzymes in prognostic prediction,we for the first time built a risk stratification model based on GSH metabolism related enzymes via LASSO Cox regression algorithm and validate its prediction performance.Patients were categorized into high-and low-risk patients according to the median of risk score.High risk score was positively correlated with suppressed immune microenvironment.As supposed,high-risk patients suffered from dismal DFS and might be the potential responders for immunotherapies.Conclusions:1.Most GSH metabolism related enzymes were upregulated in THCA and closely related to the poor prognostic outcome of cancer.2.High risk score was positively correlated with suppressed immune microenvironment.In addition,high-risk patients suffered from dismal DFS and might be the potential responders for immunotherapies.3.Expression of GSH metabolism related enzymes is conducive to instruct individualized therapies and the underlying mechanism of how GSH metabolism regulates the progression of THCA is worth deeper investigation.