Abstract
Introduction: Somatic DNA variants in the tumor suppressor gene TP53 have been reported in papillary thyroid carcinoma (PTC), Hürthle cell carcinoma (HCC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid carcinoma. However, TP53 variants are uncommon among cytologically indeterminate thyroid nodules, so their positive predictive value (PPV) for malignancy, when identified, is unknown. The original Afirma Xpression Atlas reported genomic variants from the mRNA of 511 genes, including TP53. Here we report the PPV of TP53 alterations among Afirma Genomic Sequencing Classifier (GSC) Suspicious Bethesda III/IV nodules in real-world clinical practice. Methods: A consecutive cohort of Afirma GSC Suspicious Bethesda III/IV nodules submitted to Veracyte for molecular analysis and positive for only TP53 alterations by the Xpression Atlas was identified. Local surgical pathology diagnoses were sought with IRB approval. One nodule per patient was included. Results: Thirty-eight TP53 variants were present among >13,000 Bethesda III/IV Afirma GSC Suspicious samples. Among the 22 with only a TP53 alteration, the first 16 consecutive nodules were included (7 nodules were Bethesda III and 9 nodules were Bethesda IV). Local surgical pathology diagnoses were available for 11 of these nodules. Seven nodules (64%) were malignant on surgical pathology: 3 cases of HCC, 1 PDTC, 1 follicular thyroid carcinoma (FTC), 1 follicular variant PTC, and 1 classical PTC. The mean size of malignant nodules was 3.6 cm (range 1-7.7 cm). The remaining four nodules (36%) were benign on surgical pathology, with a mean size of 2.6 cm (range 1.5-4.2 cm). Benign cases included 2 follicular adenomas (FA), 1 Hürthle cell adenoma (HCA), and 1 adenomatoid nodule (AN). Seven different TP53 variants were identified, and only one was observed at least 3 times (TP53: p.R248Q in 2 cases of HCC and 1 adenomatoid nodule). Given the small numbers, meaningful estimates of the variants’ individual PPVs could not be calculated. Conclusions: TP53 variants among Afirma GSC Suspicious Bethesda III/IV nodules are very rare and associated with malignancy in 64% of nodules based on local pathology review. A broad range of both benign and malignant neoplasms, including HCC, PDTC, FTC, PTC, FA, HCA, and AN, were reported among nodules with TP53 alterations. The prognostic value of finding an isolated TP53 variant in Afirma Suspicious nodules remains unknown.