Molecular Profiling of 50 734 Bethesda III-VI Thyroid Nodules by ThyroSeq v3: Implications for Personalized Management

Simion Chiosea, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Steven P. Hodak, NYU Robert I. Grossman School of Medicine, NYU Langone Health, New York, NY 12297, USA.
Linwah Yip, Division of Endocrine Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Devaprabu Abraham, Division of Endocrinology, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, USA.
Chelsey Baldwin, Division of Endocrinology & Metabolism, George Washington University, Washington, DC 20037, USA.
Zubair Baloch, Perelman School of Medicine Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA 19103, USA.
Seza A. Gulec, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA.
Zeina C. Hannoush, Division of Endocrinology, Diabetes and Metabolism. University of Miami, Miller School of Medicine, Miami, FL 33146, USA.
Bryan R. Haugen, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Lija Joseph, Lowell General Hospital, Boston University and Tufts University, Lowell, MA 01854, USA.
Atil Y. Kargi, Division of Endocrinology, Diabetes and Metabolism. University of Miami, Miller School of Medicine, Miami, FL 33146, USA.
Elham Khanafshar, Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
Masha J. Livhits, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Bryan McIver, Moffitt Cancer Center, Tampa, FL 33612, USA.
Kepal Patel, NYU Robert I. Grossman School of Medicine, NYU Langone Health, New York, NY 12297, USA.
Snehal G. Patel, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30342, USA.
Gregory W. Randolph, Harvard Medical School, Boston, MA 02115, USA.
Ashok R. Shaha, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Jyotirmay Sharma, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30342, USA.
Nikolaos Stathatos, Harvard Medical School, Boston, MA 02115, USA.
Annemieke van Zante, Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
Sally E. Carty, Division of Endocrine Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Yuri E. Nikiforov, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Marina N. Nikiforova, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

Document Type

Journal Article

Publication Date

10-18-2023

Journal

The Journal of clinical endocrinology and metabolism

Volume

108

Issue

11

DOI

10.1210/clinem/dgad220

Keywords

fine needle aspirate; gene fusions; genetic analysis; mutations; thyroid cancer; thyroid nodule

Abstract

CONTEXT: Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine needle aspiration (FNA) samples has not been reported. OBJECTIVE: To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. METHODS: This retrospective analysis of FNA samples, tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier at UPMC Molecular and Genomic Pathology laboratory, analyzed the prevalence of diagnostic, prognostic, and targetable genetic alterations in a total of 50 734 BCIII-VI nodules from 48 225 patients. RESULTS: Among 50 734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alterations. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.9% of cases. CONCLUSION: In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutations and targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.

Department

Medicine

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