Prognostic Classifier Based on Genome-Wide DNA Methylation Profiling in Well-Differentiated Thyroid Tumors

Abstract Even though the majority of well-differentiated thyroid cancer (WDTC) is indolent, a number of cases display an aggressive behavior. Cumulative evidences have suggested that the deregulation of DNA methylation has the potential to point out molecular markers associated with worse prognosis. To identify a prognostic epigenetic signature in thyroid cancer. Genome-wide DNA methylation assays (450k platform, Illumina) were performed in a cohort of 50 non-neoplastic thyroid tissues (NT), 17 benign thyroid lesions (BTL) and 74 thyroid carcinomas (60 papillary, 8 follicular, 2 Hurthle cell, 1 poorly differentiated and 3 anaplastic). A prognostic classifier for WDTC was developed using diagonal linear discriminant analysis. The results were compared with the Cancer Genome Atlas (TCGA) database. A specific epigenetic profile was detected according to each histological subtype. Benign lesions and follicular carcinomas showed a greater number of methylated CpG in comparison with NT, whereas hypomethylation was predominant in papillary and undifferentiated carcinomas. A prognostic classifier based on 21 DNA methylation probes was able to predict poor outcome in patients with WDTC (Sensitivity: 63%; Specificity: 92% for internal data; Sensitivity: 64%; Specificity: 88% for TCGA data). High-risk score based on the classifier was considered an independent factor of poor outcome (Cox Regression, P