Characterization of Subtypes of BRAF-Mutant Papillary Thyroid Cancer Defined by Their Thyroid Differentiation Score

Abstract

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.