Characterization of subtypes of BRAF-mutant papillary thyroid cancer defined by their thyroid differentiation score Journal Article


Authors: Boucai, L.; Seshan, V.; Williams, M.; Knauf, J. A.; Saqcena, M.; Ghossein, R. A.; Fagin, J. A.
Article Title: Characterization of subtypes of BRAF-mutant papillary thyroid cancer defined by their thyroid differentiation score
Abstract: Context: The BRAFV600E mutation has been associated with more advanced clinical stage in papillary thyroid cancer (PTC) and decreased responsiveness to radioiodine (RAI). However, some BRAF mutant PTCs respond to RAI and have an indolent clinical behavior suggesting the presence of different subtypes of BRAF mutant tumors with distinct prognosis. Objective: To characterize the molecular and clinical features of 2 subtypes of BRAF-mutant PTCs defined by their degree of expression of iodine metabolism genes. Design: 227 BRAF-mutant PTCs from the Cancer Genome Atlas Thyroid Cancer study were divided into 2 subgroups based on their thyroid differentiation score (TDS): BRAF-TDShi and BRAF-TDSlo. Demographic, clinico-pathological, and molecular characteristics of the 2 subgroups were compared. Results: Compared to BRAF-TDShi tumors (17%), BRAF-TDSlo tumors (83%) were more frequent in blacks and Hispanics (6% vs 0%, P = 0.035 and 12% vs 0%, P = 0.05, respectively), they were larger (2.95 ± 1.7 vs 2.03 ± 1.5, P = 0.002), with more tumor-involved lymph nodes (3.9 ± 5.8 vs 2.0 ± 4.2, P = 0.042), and a higher frequency of distant metastases (3% vs 0%, P = 0.043). Gene set enrichment analysis showed positive enrichment for RAS signatures in the BRAF-TDShi cohort, with corresponding reciprocal changes in the BRAF-TDSlo group. Several microRNAs (miRs) targeting nodes in the transforming growth factor β (TGFβ)-SMAD pathway, miR-204, miR-205, and miR-144, were overexpressed in the BRAF-TDShi group. In the subset with follow-up data, BRAF-TDShi tumors had higher complete responses to therapy (94% vs 57%, P < 0.01) than BRAF-TDSlo tumors. Conclusion: Enrichment for RAS signatures, key genes involved in cell polarity and specific miRs targeting the TGFβ-SMAD pathway define 2 subtypes of BRAF-mutant PTCs with distinct clinical characteristics and prognosis. © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Keywords: genetics; mutation; microrna; transforming growth factor beta; pathology; radioactive iodine; iodine radioisotopes; thyroid neoplasms; micrornas; b raf kinase; thyroid tumor; proto-oncogene proteins b-raf; braf protein, human; humans; human; thyroid cancer, papillary; braf-mutant thyroid cancer; thyroid differentiation score; mirn204 microrna, human
Journal Title: Journal of Clinical Endocrinology and Metabolism
Volume: 107
Issue: 4
ISSN: 0021-972X
Publisher: Oxford University Press  
Date Published: 2022-04-01
Start Page: 1030
End Page: 1039
Language: English
DOI: 10.1210/clinem/dgab851
PUBMED: 34897468
PROVIDER: scopus
PMCID: PMC8947218
DOI/URL:
Notes: Article -- Export Date: 2 May 2022 -- Source: Scopus
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  1. Venkatraman Ennapadam Seshan
    385 Seshan
  2. James A Fagin
    181 Fagin
  3. Ronald A Ghossein
    486 Ghossein
  4. Laura   Boucai
    48 Boucai
  5. Mahesh   Saqcena
    11 Saqcena