Identification and validation of m6A RNA methylation regulators with clinical prognostic value in Papillary thyroid cancer

Xinyi Wang,Shuyong Zhang,Xiaorui Fu,Chengfeng Xiong,Yunxia Lv,Junjia Zhang

doi:10.1186/s12935-020-01283-y

Abstract

BackgroundPapillary thyroid cancer (PTC) is a type of malignant tumor with excellent prognosis, accounting for more than 80% of thyroid cancer. Recently, numerous studies illustrated the importance of N6-methyladenosine (m6A) RNA modification to tumorigenesis, but it has never been reported in PTC.MethodsWe downloaded data from The Cancer Genome Atlas (TCGA) and analyzed RNA expression, single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) of 19 m6A RNA methylation regulators in PTC. Then we used nonnegative matrix factorization (NMF) to cluster patients into two m6A subtypes and compared them in overall survival (OS) and disease-free survival (DFS). The Weighted correlation network analysis (WGCNA) and univariate Cox proportional hazard model (CoxPH) were used to select genes for the construction of a m6A-related signature. The accuracy and prognostic value of this signature were validated by using receiver operating characteristic (ROC) curves, K-M (Kaplan–Meier) survival analysis, univariant and multivariant analyses.ResultsCNVs and differential expression of m6A regulators were observed in PTC patients. Especially IGF2BP2 (Insulin-like growth factor 2 mRNA binding protein 2), which was most significantly overexpressed in tumor tissue. We chose 4 genes in the m6A-related module from WGCNA: IGF2BP2, STT3A, MTHFD1 and GSTM4, and used them to construct a m6A-related signature. The prognostic value of this signature was validated, and risk scores provided by the signature was the independent prognostic factor for PTC. A nomogram was also provided for clinical usage.ConclusionsWe performed a comprehensive evaluation of the m6A RNA modification landscape of PTC and explored its underlying mechanisms. Our m6A-related signature was of great significance in predicting the DFS of patients with PTC. And IGF2BP2 was a gene worthy for further analysis as its strong correlation with DFS and clinical phenotypes of PTC.

Highlights

We evaluated the correlation between the copy number and mRNA level of 19 m6A regulators, and found higher copy number of 4 genes were corresponded with higher expression level: ALKBH5 (P = 0.001), METTL16 (P = 2.287e−04), WTAP (P = 0.003) and YTHDF1 (P = 0.009) (Fig. 2d–g)
There was no statistical difference between the overall survival (OS) of cluster 1 and cluster 2 (P = 0.056, Fig. 3d). These results demonstrated that m 6A RNA methylation may have strong correlation with disease-free survival (DFS) of Papillary thyroid cancer (PTC) patients
As shown in the heatmap, IGF2BP1, WTAP, FTO, IGF2BP3 and ALKBH5 had higher expression level in cluster 2, while IGF2BP2, RBM15B, HNRNPC were significantly downregulated in cluster 2 (Fig. 3e, Additional file 7: Table S5). We found these 2 clusters were different in extrathyroidal extension (P < 0.01), T (P < 0.01) and N (P < 0.001) classifications, suggesting m 6A RNA methylation may related to clinical phenotypes and progression of PTC

Summary

Introduction

Papillary thyroid cancer (PTC) is a type of malignant tumor with excellent prognosis, accounting for more than 80% of thyroid cancer. Thyroid cancer is one of malignant tumors whose incidence are rapidly increasing in the world for both men and women. It can be classified into several subtypes: PTC, follicular thyroid cancer (FTC) and medullary thyroid cancer (MTC) [1]. PTC is the most common type of thyroid cancer, accounting for more than 80% of all cases. Prognosis of patients with PTC is excellent, with 5-year-survival rate over 97% [2]. The 10-year and 15-year survival rates of papillary microcarcinoma, PTC which is smaller than 1 cm, are even over 99% [3].

Methods

Results

Conclusion