Abstract

BackgroundPapillary thyroid carcinoma (PTC) is the most common thyroid cancer. While many patients survive, a portion of PTC cases display high aggressiveness and even develop into refractory differentiated thyroid carcinoma. This may be alleviated by developing a novel model to predict the risk of recurrence. Ferroptosis is an iron-dependent form of regulated cell death (RCD) driven by lethal accumulation of lipid peroxides, is regulated by a set of genes and shows a variety of metabolic changes. To elucidate whether ferroptosis occurs in PTC, we analyse the gene expression profiles of the disease and established a new model for the correlation.MethodsThe thyroid carcinoma (THCA) datasets were downloaded from The Cancer Genome Atlas (TCGA), UCSC Xena and MisgDB, and included 502 tumour samples and 56 normal samples. A total of 60 ferroptosis related genes were summarised from MisgDB database. Gene set enrichment analysis (GSEA) and Gene set variation analysis (GSVA) were used to analyse pathways potentially involving PTC subtypes. Single sample GSEA (ssGSEA) algorithm was used to analyse the proportion of 28 types of immune cells in the tumour immune infiltration microenvironment in THCA and the hclust algorithm was used to conduct immune typing according to the proportion of immune cells. Spearman correlation analysis was performed on the ferroptosis gene expression and the correlation between immune infiltrating cells proportion. We established the WGCNA to identify genes modules that are highly correlated with the microenvironment of immune invasion. DEseq2 algorithm was further used for differential analysis of sequencing data to analyse the functions and pathways potentially involving hub genes. GO and KEGG enrichment analysis was performed using Clusterprofiler to explore the clinical efficacy of hub genes. Univariate Cox analysis was performed for hub genes combined with clinical prognostic data, and the results was included for lasso regression and constructed the risk regression model. ROC curve and survival curve were used for evaluating the model. Univariate Cox analysis and multivariate Cox analysis were performed in combination with the clinical data of THCA and the risk score value, the clinical efficacy of the model was further evaluated.ResultsWe identify two subtypes in PTC based on the expression of ferroptosis related genes, with the proportion of cluster 1 significantly higher than cluster 2 in ferroptosis signature genes that are positively associated. The mutations of Braf and Nras are detected as the major mutations of cluster 1 and 2, respectively. Subsequent analyses of TME immune cells infiltration indicated cluster 1 is remarkably richer than cluster 2. The risk score of THCA is in good performance evaluated by ROC curve and survival curve, in conjunction with univariate Cox analysis and multivariate Cox analysis results based on the clinical data shows that the risk score of the proposed model could be used as an independent prognostic indicator to predict the prognosis of patients with papillary thyroid cancer.ConclusionsOur study finds seven crucial genes, including Ac008063.2, Apoe, Bcl3, Acap3, Alox5ap, Atxn2l and B2m, and regulation of apoptosis by parathyroid hormone-related proteins significantly associated with ferroptosis and immune cells in PTC, and we construct the risk score model which can be used as an independent prognostic index to predict the prognosis of patients with PTC.

Highlights

  • Thyroid cancer (TC) is the most common endocrine malignant tumour worldwide and its incidence has been increasing [1]

  • The risk score of thyroid carcinoma (THCA) is in good performance evaluated by Receiver operating characteristic (ROC) curve and survival curve, in conjunction with univariate Cox analysis and multivariate Cox analysis results based on the clinical data shows that the risk score of the proposed model could be used as an independent prognostic indicator to predict the prognosis of patients with papillary thyroid cancer

  • Our study finds seven crucial genes, including Ac008063.2, Apoe, Bcl3, Acap3, Alox5ap, Atxn2l and B2m, and regulation of apoptosis by parathyroid hormone-related proteins significantly associated with ferroptosis and immune cells in Papillary thyroid carcinoma (PTC), and we construct the risk score model which can be used as an independent prognostic index to predict the prognosis of patients with PTC

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Summary

Introduction

Thyroid cancer (TC) is the most common endocrine malignant tumour worldwide and its incidence has been increasing [1]. There is a 3-fold higher incidence rate of TC in women, which is about 10.1 per 100,000 cases, representing one in every 20 cancers diagnosed among women [3]. Differentiated thyroid cancer, which originates from thyroid follicular epithelial cells, accounts for more than 95% of TC, among which papillary thyroid carcinoma (PTC) constitutes more than 85% of cases [8, 9]. A portion of PTC cases display high aggressiveness and even develop into refractory differentiated thyroid carcinoma. This may be alleviated by developing a novel model to predict the risk of recurrence. To elucidate whether ferroptosis occurs in PTC, we analyse the gene expression profiles of the disease and established a new model for the correlation

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