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Detection of Serum Deoxyribonucleic Acid Methylation Markers: A Novel Diagnostic Tool for Thyroid Cancer

Division of Endocrinology and Metabolism, Departments of Medicine (S.H., M.E., D.L., D.S.C., P.W.L., M.X.), Otolaryngology-Head and Neck Surgery (R.P.T., M.B., A.L.C., D.S.), and Surgery (A.P.T.), the Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Division of Endocrinology and Metabolism (S.B.), the Johns Hopkins Bayview Medical Center, Baltimore, Maryland 21224; and Division of Endocrinology and Metabolism (D.S.C.), Sinai Hospital of Baltimore, Baltimore, Maryland 21215

Address all correspondence and requests for reprints to: Mingzhao Xing, M.D., Ph.D., Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287. E-mail: mxing1{at}jhmi.edu.

Context: Serum DNA methylation markers may potentially be useful in diagnosing thyroid cancer and monitoring its recurrence.

Objective: The objective of the study was to assess the utility of serum DNA methylation as a diagnostic test for patients with thyroid nodules and a monitoring test to detect thyroid cancer recurrence in previously treated patients.

Design, Setting, and Subjects: Using real-time quantitative methylation-specific PCR, we analyzed the methylation status of five genes (CALCA, CDH1, TIMP3, DAPK, and RARß₂) on 96 bisulfite-treated serum DNA samples isolated preoperatively from either solid thyroid nodule patients or patients in follow-up for history of treated thyroid cancer.

Main Outcome Measure: Diagnostic sensitivity, specificity, and accuracy of serum DNA methylation marker for thyroid cancer were measured.

Results: For the patients with thyroid nodules, when a positive result was defined by a serum methylation level above the appropriately chosen cutoff value for any one of the five genes, the preoperative diagnostic sensitivity for thyroid cancer was 68% (26 of 38), the specificity was 95% (18 of 19), and the overall preoperative diagnostic accuracy was 77%, with positive and negative predictive values of 96 and 60%, respectively. In a subset of patients with cytologically indeterminate thyroid nodules, serum DNA methylation testing could correctly diagnose eight of 11 (73%) cancers and four of four (100%) benign tumors, with a diagnostic accuracy of 80%. We also analyzed these serum DNA methylation markers in 39 previously treated thyroid cancer patients. Among the 10 patients proved to have recurrent disease by conventional measures, seven (70%) were positive on methylation testing. Among the 29 patients who had no corroboration of residual or recurrent disease by conventional studies, six (21%) were positive for serum DNA methylation markers.

Conclusions: We have demonstrated the potential usefulness of serum DNA methylation markers as a novel tool for differential diagnosis of solid thyroid nodules and thyroid cancer recurrence monitoring.

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