Highly Sensitive and Specific Molecular Test for Mutations in the Diagnosis of Thyroid Nodules: A Prospective Study of BRAF-Prevalent Population

Abstract

Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70–80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.

Clinical value of multi-gene testing in distinguishing benign and malignant thyroid nodules

“…As previously reported by Song et al [31] found that the PAX8/PPARG gene mutation rate in Asians was much lower than in westerners. Consistently, PAX8/PPARG gene mutations were not reported in the multi-gene study by Yoon Young Cho et al [14]…”

“…It is worth noting that different races may vary in molecular alterations in this type of tumor. Previous research showed that the common mutated gene: BRAF V600E , ranged from 29% to 83% (mean: 45%) in papillary thyroid cancer (PTC), [11,12] with higher alternation frequency in Asian people (70-80%) [13,14] and lower mutations in the Americans (40-50%), [15] although the rate has increased in the recent decade. [16] Given the growing need for individualized diagnosis and therapy, neither mere cytology nor single-gene testing is satisfactory for clinical practice.…”

Malignancy Rate of Bethesda Class III Thyroid Nodules Based on the Presence of Chronic Lymphocytic Thyroiditis in Surgical Patients

“…In addition, FVPTC was the dominant pathology (61%) in malignancies, and the positive rate of BRAF V600E mutation was low (4% of all tumors) because thyroid nodules with AUS/FLUS cytology were investigated. In the literature, RAS is the most prevalent mutation and FVPTC, rather than classic PTC, is the most common malignancy in nodules with indeterminate cytology ( 28 , 29 ).…”

Deep learning-based multifeature integration robustly predicts central lymph node metastasis in papillary thyroid cancer

“…PTC is usually characterized by chromosomal rearrangements of RET or point mutations in the RAS or BRAF proto-oncogene, and mutations in the BRAF, RAS, or RET genes are found in nearly 70% of PTC cases [19,29]. Of these, BRAF mutations are seen in 60%-70% of PTCs, making them the most common mutations in PTC [30,31]. Yan et al showed that 1715 of 2048 patients with PTC had BRAF V600E mutations, with a mutation rate of 83.7% [32].…”