Genetic Analysis of Locally Advanced Well-Differentiated Thyroid Cancer: Clinical Prognostic Implications

Abstract

Background and Objectives: Despite the usually favorable prognosis of well-differentiated thyroid cancer (WDTC) following appropriate treatment, advanced T-staged WDTCs are associated with poor prognosis. This study focused on identifying genes associated with the prognosis of locally advanced WDTC by analyzing a The Cancer Genome Atlas cohort. Subjects and Method: We analyzed the data of 501 patients with WDTC and classified them into two subgroups: pathological T4 stage (Cluster 1) or T1-3 stage (Cluster 2). We compared the mRNA expressions of thyroid cancer-related genes, and the somatic mutation frequencies of various cancer genes between the two subgroups. Results: Cluster 1 included 23 patients (papillary=21/follicular-variant papillary thyroid cancer [FVPTC]=2) and Cluster 2 478 patients (papillary=371/FVPTC=100/others=7). Cluster 1 showed worse overall and disease-free survival than Cluster 2 (p<0.05 and p=0.12, respectively). Patients with pT4 stage had about a 1.8-fold increased risk of overall recurrence or death. MET, SERPINA1, TIMP1, PROS1, FN1, CDKN2A, and CDKN2B were significantly elevated while TG, DNAH9, TFF3, CRABP1, TPO, JAK2, KIT, KDR, and NFE2L2 were significantly lower in Cluster 1 (all, p<0.05 and adjusted p<0.05). A TERT, EIF1AX, and ATM showed significantly frequent somatic mutations in Cluster 1 when compared to Cluster 2. We also identified seven pathways related to 16 genetic markers. Conclusion: Locally advanced WDTC presented 16 genetic alterations. We identified somatic mutations associated with local invasion transformation. Relevant pathways related to the 16 genetic markers could be therapeutic targets. Genetic analysis of locally advanced WDTC may be used to predict clinical applications in patient survival.