A Key Biomarker lnc-ABCA12-5:2 Compensating Diagnostic Deficiencies for Indeterminate Thyroid Nodules and Genetically Wild-Type Thyroid Malignancies

Background: Preoperative fine-needle aspiration (FNA) cytology and conventional genetic testing often fail on indeterminate thyroid nodules and malignancies lacking typical driver mutations. We validated two candidate lncRNAs, lnc-ABCA12-5:2 and lnc-MPEG1-1:1, initially screened in papillary thyroid carcinoma (PTC) tissues, using preoperative FNA and postoperative formalin-fixed paraffin-embedded (FFPE) specimens. Methods: Diagnostic performance was assessed in two independent cohorts encompassing diverse Bethesda categories and thyroid carcinoma subtypes. Molecular correlations and clinicopathological associations were also examined. Results: Both lncRNAs exhibited excellent diagnostic efficacy for PTC in preoperative FNA samples (area under the curve values: 0.923 and 0.968; sensitivity > 0.85; specificity > 0.90). lnc-ABCA12-5:2 achieved 100% specificity and 100% positive predictive value in Bethesda III-IV nodules, and was an independent predictor alongside BRAF V600E. Integrating lnc-ABCA12-5:2 with BRAF V600E testing raised diagnostic accuracy in indeterminate nodules from 89.5% to 95.0% (95.7% sensitivity, 92.9% specificity). lnc-ABCA12-5:2 positivity increased progressively with higher Bethesda grades (p-trend < 0.001), achieved 100% positivity in high-grade aggressive carcinomas, and remained elevated (83.6%) in genetically wild-type malignant nodules. Its expression strongly correlated with aggressive molecular signatures (including TERT, TP53, PI3K/AKT/PTEN alterations), yielding 100% positivity in such cases. In vitro cellular functional assays further confirmed that lnc-ABCA12-5:2 overexpression significantly promoted cell proliferation, colony formation, and migration in PTC cell lines. Conclusions: lnc-ABCA12-5:2 and lnc-MPEG1-1:1 are robust preoperative biomarkers for PTC. lnc-ABCA12-5:2 fills critical diagnostic gaps in indeterminate and genetically wild-type thyroid malignancies, and correlates with aggressive tumor molecular profiles, underscoring its translational potential for clinical risk stratification.