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

• Published in: The journal of clinical endocrinology and metabolism Vol. 102; no. 11; pp. 4089 - 4099
• Main Authors: Bisarro dos Reis, Mariana, Barros-Filho, Mateus Camargo, Marchi, Fábio Albuquerque, Beltrami, Caroline Moraes, Kuasne, Hellen, Pinto, Clóvis Antônio Lopes, Ambatipudi, Srikant, Herceg, Zdenko, Kowalski, Luiz Paulo, Rogatto, Silvia Regina
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01-11-2017; Copyright Oxford University Press; Oxford University Press
• Subjects: Adenocarcinoma, Follicular - genetics; Adenocarcinoma, Follicular - pathology; Adult; Carcinoma, Papillary - genetics; Carcinoma, Papillary - pathology; Clinical s; CpG islands; Deoxyribonucleic acid; Deregulation; Discriminant analysis; DNA; DNA fingerprinting; DNA Methylation; DNA probes; Epigenesis, Genetic; Epigenetics; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genome-Wide Association Study - methods; Genomes; Humans; Lesions; Male; Microarray Analysis; Middle Aged; Probes; Prognosis; Retrospective Studies; Sensitivity; Thyroid cancer; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Transcriptome; Tumors
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2017-00881

Abstract
Context
Even though the majority of well-differentiated thyroid carcinoma (WDTC) is indolent, a number of cases display an aggressive behavior. Cumulative evidence suggests that the deregulation of DNA methylation has the potential to point out molecular markers associated with worse prognosis.
Objective
To identify a prognostic epigenetic signature in thyroid cancer.
Design
Genome-wide DNA methylation assays (450k platform, Illumina) were performed in a cohort of 50 nonneoplastic thyroid tissues (NTs), 17 benign thyroid lesions (BTLs), and 74 thyroid carcinomas (60 papillary, 8 follicular, 2 Hürthle cell, 1 poorly differentiated, and 3 anaplastic). A prognostic classifier for WDTC was developed via diagonal linear discriminant analysis. The results were compared with The Cancer Genome Atlas (TCGA) database.
Results
A specific epigenetic profile was detected according to each histological subtype. BTLs and follicular carcinomas showed a greater number of methylated CpG in comparison with NTs, 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 < 0.001).
Conclusions
The methylation profile of thyroid lesions exhibited a specific signature according to the histological subtype. A meaningful algorithm composed of 21 probes was capable of predicting the recurrence in WDTC.
An epigenetic signature of thyroid lesions is described based on the DNA methylation analysis. An algorithm was developed to predict recurrence, which has potential to be used in the clinical practice.