Alterations in gene expression associated with invasion of RAS-mutant thyroid tumors and their potential diagnostic and therapeutic utility.

Summary

RNA-seq of 48 RAS-mutant thyroid tumors revealed distinct expression profiles between invasive and non-invasive lesions. A 6-gene panel (CA12, CD44, LRP4, ECM1, FN1, CRABP1) plus nodule size predicted invasion in RAS-mutant FNA samples with 95% sensitivity and 89% specificity. Targeting CA12 reduced invasion in vitro and arrested growth in RAS-mutant xenografts.

Key Findings

• Invasive vs non-invasive RAS-mutant tumors exhibited distinct RNA-seq expression profiles.
• A 6-gene panel (CA12, CD44, LRP4, ECM1, FN1, CRABP1) plus nodule size predicted invasion in FNA samples (95% sensitivity, 89% specificity).
• siRNA and chemical inhibition of CA12 reduced invasion in RAS-mutant thyroid cells; CA12 inhibitors arrested growth in RAS-mutant xenografts.

Clinical Implications

Preoperative FNA-based testing using the 6-gene panel could identify invasive RAS-mutant nodules to guide extent of surgery and surveillance. CA12 inhibition represents a potential targeted therapy for invasive RAS-mutant thyroid tumors.

Limitations

• Moderate sample size from a single research network; external multicenter validation is needed.
• Classifier limited to RAS-mutant nodules; applicability to non-RAS tumors is unknown.

Future Directions

Prospective multicenter validation of the FNA classifier, pharmacologic optimization of CA12 inhibitors, and evaluation of combination strategies in RAS-mutant thyroid cancer.