Identification of the Prognostic Signature Associated With Tumor Immune Microenvironment of Uterine Corpus Endometrial Carcinoma Based on Ferroptosis-Related Genes

Abstract

Background: Uterine corpus endometrial carcinoma (UCEC) is the sixth most common cancer worldwide. Ferroptosis plays an important role in malignant tumors. However, the study of ferroptosis in the endometrial carcinoma remains blank.Methods: First, we constructed a ferroptosis-related signature based on the expression profiles from The Cancer Genome Atlas database. Then, patients were divided into the high-risk and low-risk groups based on this signature. The signature was evaluated by Kaplan–Meier analysis and receiver operating characteristic (ROC) analysis. We further investigated the relationship between this signature and immune microenvironment via CIBERSORT algorithm, ImmuCellAI, MAF, MSI sensor algorithm, GSEA, and GDSC.Results: This signature could be an independent prognostic factor based on multivariate Cox regression analysis. GSEA revealed that this signature was associated with immune-related phenotype. In addition, we indicated the different status of immune infiltration and response to the immune checkpoint between low-risk and high-risk groups. Patients in the low-risk group were more likely to present with a higher expression of immune checkpoint molecules and tumor mutation burden. Meanwhile, the low-risk patients showed sensitive responses to chemotherapy drugs.Conclusion: In summary, the six ferroptosis-related genes signature could be used in molecular subgrouping and accurately predict the prognosis of UCEC.

Establishing a Prognostic Signature Based on Epithelial–Mesenchymal Transition-Related Genes for Endometrial Cancer Patients

“…The response to chemotherapy and small-molecule drugs in UCEC patients was determined using a public database called Genomics of Drug Sensitivity in Cancer (GDSC; https://www.cancerrxgene.org). The half-maximal inhibitory concentration (IC50) was estimated, which represented the drug response (17). The NCI-60 database is currently the most widely used for cancer drug testing, which was accessed through the CellMiner interface (https://discover.nci.…”

Prediction of Prognosis in Patients With Endometrial Carcinoma and Immune Microenvironment Estimation Based on Ferroptosis-Related Genes

“…Therefore, ferroptosis seems to be a promising target for cancer therapy. There have been several reports on the correlation between ferroptosis-related genes (FRGs) and clinical prognosis in EC (Liu et al, 2021;Weijiao et al, 2021). Wang et al identify a 13-FRGs prognostic signature for EC.…”

Ferroptosis: Opportunities and Challenges in Treating Endometrial Cancer

“…This suggests that those who had a low score of ferroptosis are more likely to be resistant to cisplatin and paclitaxel, while those who had a high score are more likely to be resistant to erlotinib, rapamycin, and temsirolimus. Similarly, another ferroptosisrelated prognosis signature showed lower IC50 of roscovitine, vinblastine, tipifarnib, lapatinib, and other twenty-two routinely administered chemotherapy drugs in the low-risk group than the high-risk group (Liu J. et al, 2021). Moreover, quite a number of ferroptosis-associated genes are responsible for chemoresistance in ovarian cancer, as indicated by the activation of the HSPA5-GPX4 pathway, which induced ferroptosis resistance, an important reason for gemcitabine resistance (Zhu et al, 2017); by the overexpression of FANCD2, which resulted in platinum resistance, while restraining FANCD2 expression with FIGURE 2 | Association of ferroptosis-associated genes with metastasis or recurrence of endometrial cancer.…”

“…However, p53 alone does not induce ferroptosis directly. p53 is an important regulator for lipid, amino acid, glucose, nucleotide, and iron metabolism (Liu and Gu et al, 2021;Liu J. et al, 2021). Based on metabolism targets, p53 contributed to ferroptosis (Liu and Gu 2022).…”

“…Therefore, it is significant that a novel, simple, and economical molecular prognostic model be explored in predicting endometrial cancer. It is well known that abnormal ferroptosis is an important reason behind the poor prognosis of endometrial cancer, as indicated by the evidence that molecular typing based on ferroptosis-associated genes showed good prognosis predictive value: 1) the ferroptosis score, based on thirteen ferroptosis-associated genes, was established, and OS of patients with a low score of ferroptosis was superior to that of those with high score of ferroptosis (AUC = 0.726) (Wang et al, 2021b); 2) a molecular typing of endometrial cancer, based on six ferroptosisassociated genes of HMOX1, KEAP1, HSBP1, SAT1, CISD1, and GPX4, showed good 1-, 3-, and 5-year prognostic predictive value (AUC = 0.705, 0.676, and 0.713) (Liu J. et al, 2021); 3) a ferroptosis-associated gene signature with eight genes of MDM2, GPX4, PRKAA2, PRNP, SLC11A2, ATP5MC3, PHKG2, and ACO1, showed better 1-, 3-, and 5-year prognostic predictive value (AUC = 0.676, 0.797, and 0.826) than the aforementioned two ferroptosis prognosis molecular typings (Weijiao et al, 2021). Ferroptosis prognosis molecular typing possessed a comparable or superior prognosis predictive value when compared with the previous prognosis molecular typings of endometrial cancer (Table 1) (Tang et al, 2019;Yang et al, 2021b;Coll-de la Rubia et al, 2021;Huang S. et al, 2021;Lu N. et al, 2021;Pang et al, 2021;Wang Z. et al, 2021).…”