Epigenetic Imprinted Biomarker Test to Identify Malignant Thyroid Nodules

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In a Chinese study reported in the Journal of Clinical Oncology, Xu et al found that a test for epigenetic imprinted biomarkers was highly accurate in distinguishing malignant vs benign thyroid nodules.

Study Details

The multicenter study involved 550 consecutively enrolled patients with nodules assessed by fine-needle aspiration and histopathology. Quantitative chromogenic imprinted gene in situ hybridization was used to assess the allelic expression of imprinted genes SNRPN and HM13.

A grading model was developed to distinguish malignant and benign nodules in a training set of 124 postsurgical nodule samples and 32 presurgical fine-needle aspiration samples. The model was prospectively evaluated in a validation set of 394 presurgical fine-needle aspiration samples, with cytopathologic and histopathologic diagnoses on blinded central review used as the reference standard.

Key Findings

In the validation set of 394 nodules, quantitative chromogenic imprinted gene in situ hybridization identified malignancy in all 277 nodules found to be malignant on histopathology, yielding a diagnostic sensitivity of 100%. Specificity was 91.5% (107/117 nodules; 95% confidence interval [CI] = 86.4%–96.5%); positive predictive value (PPV) was 96.5% (95% CI = 94.4%–98.6%), negative predictive value (NPV) was 100%; and overall diagnostic accuracy was 97.5% (384/394 nodules; 95% CI = 95.9%–99.0%).

In analysis by Bethesda category, the test had a PPV of 96.6% (95% CI = 91.9%–100%) and NPV of 100%, with diagnostic accuracy of 97.5% (79/81 nodules; 95% CI = 94.2%–100%) for Bethesda III and IV nodules. For Bethesda V nodules, the test identified the 1 benign nodule as benign and all 33 malignant nodules as malignant. For Bethesda VI nodules, the test identified all 184 malignant nodules as malignant. For cytologically indeterminate Bethesda III, IV, and V nodules combined, the test had a PPV of 97.8% (95% CI = 94.7%–100%) and NPV of 100%, with diagnostic accuracy of 98.2% (111/113 nodules; 95% CI = 95.8%–100%).

The investigators concluded, “This imprinting biomarker-based test can effectively distinguish malignant from benign thyroid nodules. The high PPV and NPV make the test both an excellent rule-in and rule-out diagnostic tool. With such a diagnostic performance and its technical simplicity, this novel thyroid molecular test is clinically widely applicable.”

Mingzhao Xing, MD, PhD, of the School of Medicine, Southern University of Science and Technology, Shenzhen, is the corresponding author for the Journal of Clinical Oncology article. 

Disclosure: The study was supported by the National Natural Science Foundation of China, Innovation Capacity Development Plan of Jiangsu Province, Science and Technology Commission of Shanghai Municipality, and others. For full disclosures of the study authors, visit

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