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

Introduction

• Thyroid cancer will account for ~2% of all new carcinoma diagnoses in the US in 2025.³
• Approximately 40,000 new cases of thyroid cancer are diagnosed in the US each year, and ~3000 of these patients die each year.
• An estimated 5-10% of patients have advanced thyroid cancer that is unresponsive to surgical and radioiodine therapy.¹
• Retinoids influence cell growth and differentiation through retinoid receptors, retinoic acid (RAR) and retinoid X receptor (RXR).^{4-5, 7-8}
  • Six major subtypes of receptor have been identified, which are encoded by separate genes (RARα, β, γ, and RXRα, -β, -γ).
• The RXRγ isoform is undetectable in normal thyroid and variably expressed in malignant tumors, and this receptor predicts response to retinoid treatment in cell lines.²
• A phase II trial with the retinoid bexarotene was stopped prematurely due to toxicity and low efficacy.⁶

Study Aim

Hypothesis: Retinoid receptors will be differentially expressed in thyroid tumors based on (B)ethesda cytology category, Afirma GSC result, and mutational status.

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 BIII/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

• RARα
  • Lower expression in BV/VI vs GSC-B
• RARβ
  • Lower expression in BRAFV600E+ tumors
• RARγ
  • Higher mRNA expression in GSC-S and BV/VI
  • Highest expression in BRAFV600E+ tumors
• RXRα
  • Lower expression in GSC-S and Bethesda V/VI samples
  • Lower expression in samples with BRAFV600E mutation
• RXRβ
  • No differences in expression
• RXRγ
  • Higher expression in GSC-S and BV/VI versus GSC-B
  • Highest expression in BRAFV600E+ tumors

Conclusion

• RARγ and RXRγ appear to be coordinately expressed based on cytology, Afirma GSC and mutation status.
• RARγ and RXRγ expression may be driven by MAPK signaling.
• RARγ and RXRγ may be good therapeutic targets in advanced thyroid cancer.
• Future studies should evaluate the underlying mechanism of how BRAFV600E and MAPK signaling may affect RARγ and RXRγ expression.