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Genetic Classification of Benign and Malignant Thyroid Follicular Neoplasia Based on a Three-Gene Combination

Clinical Cancer Genetics Program (F.W., C.E.), Human Cancer Genetics Program (F.W., M.D.R., C.E.), Comprehensive Cancer Center (M.S., M.D.R., C.E.), and Divisions of Endocrinology and Metabolism (M.S., M.D.R.) and Human Genetics (C.E.), Department of Internal Medicine, Department of Molecular Virology, Immunology and Medical Genetics (F.W., C.E.), Division of Epidemiology and Biometrics (L.S.), Department of Pathology (C.D.M.), The Ohio State University, Columbus, Ohio 43210; Department of General Surgery and Transplantation (F.W., A.F., C.E.B.), University of Essen, 45122 Essen, Germany; Department of Internal Medicine (F.S.), Hospital Bad Oeynhausen, 32545 Bad Oeynhausen, Germany; Division of Medical Genetics (M.A.A.), University of Leicester, Leicester LE1 7RH, United Kingdom; and Cancer Research UK Human Cancer Genetics Research Group (C.E.), University of Cambridge, Cambridge CB2 1XZ, United Kingdom

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., Human Cancer Genetics Program, The Ohio State University, 420 West 12th Avenue, Suite 690 Tzagournis Medical Research Facility, Columbus, Ohio 43210. E-mail: eng.25{at}osu.edu.

Thyroid carcinoma is a common endocrine cancer with a favorable prognosis if subjected to timely treatment. However, the clinical identification of follicular thyroid carcinoma (FTC) among patients with benign thyroid nodules is still a challenge. Preoperative fine needle aspiration-based cytology cannot always differentiate follicular carcinomas from benign follicular neoplasias. Because current methods fail to improve preoperative diagnosis of thyroid nodules, new molecular-based diagnoses should be explored. We conducted a microarray-based study to reveal the genetic profiles unique to FTC and follicular adenomas (FAs), to identify the most parsimonious number of genes that could accurately differentiate between benign and malignant follicular thyroid neoplasia. We confirmed our data by quantitative RT-PCR and immunohistochemistry in two independent validation sets with a total of 114 samples. We were able to identify three genes, cyclin D2 (CCND2), protein convertase 2 (PCSK2), and prostate differentiation factor (PLAB), that allow the accurate molecular classification of FTC and FA. Two independent validation sets revealed that the combination of these three genes could differentiate FTC from FA with a sensitivity of 100%, specificity of 94.7%, and accuracy of 96.7%. In addition, our model allowed the identification of follicular variants of papillary thyroid carcinoma with an accuracy of 85.7%. Three-gene profiling of thyroid nodules can accurately predict the diagnosis of FTC and FA with high sensitivity and specificity, thus identifying promising targets for further investigation to ultimately improve preoperative diagnosis.

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