MON-392 Retinoic Acid Receptor (RAR) and Retinoid X Receptor (RXR) Expression in Preoperative Thyroid Tumor Samples

Abstract Disclosure: J. Lin: None. R. Conard: None. W.S. Goldner: None. M. Alshalalfa: Veracyte, Inc. Y. Hao: Veracyte, Inc. J.P. Klopper: Veracyte, Inc. B.R. Haugen: Veracyte, Inc.. Introduction: Retinoids (Vitamin A derivatives) influence cell growth and differentiation through activation of the different retinoid receptor isoforms (RARα, -β, -γ and RXRα, -β, -γ). This aim of this study is to characterize the expression level of retinoid receptors in preoperative thyroid tissue samples sent for Afirma molecular testing based on the (B)ethesda cytology category and presence of genomic variants and fusions. Methods: mRNA expression of the six retinoic acid (RAR) and retinoid X receptor (RXR) isoforms was analyzed across thyroid nodules sent for Afirma testing. Differential expression was explored across a cohort of nodules with B III/IV cytology and Afirma benign (GSC-B) or suspicious (GSC-S) categories, BV/VI nodules, and relative to BRAFV600E status. Another cohort with TERT promoter mutational status was analyzed along with expressed variant and fusion alterations as well as other genomic markers of tumor aggressiveness. Results: In the first cohort (n=47,695), relative to GSC-B nodules (n=30,259), the most notable differential expression was in RXRγ, where expression levels in GSC-S and BV/VI nodules were significantly higher, and even higher in the presence of the BRAFV600E mutation. Conversely, RXRα expression was lower in GSC-S and BV/VI nodules relative to GSC-B nodules, and even lower in the presence of BRAFV600E, and RXRβ was largely unchanged. The RAR isoforms followed the same increased expression pattern, though not to the extent of RXRγ in GSC-S and BV/VI nodules. RXRγ was significantly higher in nodules harboring alterations in the MAPK pathway (BRAFV600E, BRAF fusion, RET/ALK/NTRK fusions, BRAFK601E, and RAS variants) compared to GSC-B and was highest in BRAF-like alterations, followed by RAS-like alterations, and relatively lowest in nonBRAF-nonRAS-like alterations. Within the second cohort (TERT promoter tested) of nodules (n=8,970), both RXRγ and RARγ were higher in samples with the BRAFV600E mutation. Relative to BRAFV600E negative and TERT negative samples, there was no expression difference between samples with BRAFV600E alone or with concomitant TERT mutations. RXRγ and RARγ expression was higher in samples with BRAFV600E in isolation compared to TERT mutations in isolation. Finally, RXRγ expression was correlated with ERK activity (r=0.53), follicular mesenchymal transition (FMT) activity (r=0.44) and the BRAF-RAS (BRS) score (r=-0.46). Conclusion: Overexpression of the γ isoform of RAR and particularly RXR is correlated with higher risk molecular alterations. Whether this observation may serve as an additional prognostic marker or therapeutic target will require further studies with histopathology and clinical follow-up outcomes. Presentation: Monday, July 14, 2025