Profile of BRAFV600E, BRAFK601E, NRAS, HRAS, and KRAS Mutational Status, and Clinicopathological Characteristics of Papillary Thyroid Carcinoma in Indonesian National Referral Hospital

Abstract

Introduction BRAF V600E and RAS mutations are the most common gene mutations in papillary thyroid carcinoma (PTC) that may be correlated with its biological behavior. There are still limited data about BRAF V600E and RAS mutations in Indonesia. This study aims to determine the prevalence of BRAF V600E and RAS mutations, and their association with clinicopathologic characteristics. Methods Patients who had total thyroidectomy from 2019 to 2021 and those who met our study criteria underwent PCR and DNA sequencing analysis for BRAF V600E, BRAF K601E, exon 2 and 3 of NRAS, HRAS , and KRAS . Analyses were performed to determine the associations of BRAF V600E and RAS mutations with clinicopathologic characteristics. Results Of 172 PTC patients, BRAF V600E mutation was observed in 37.8% of the patients and RAS mutations were found in 21.5%. One patient harbored BRAF K601E mutation. There was a significant association of BRAF V600E with a high-stage (p = 0.033, OR: 3.279; 95% CI: 1.048–10.259), tall-cell variants (p ≤0.001, OR: 41.143; 95% CI: 11.979–141.308), non-encapsulated (p = 0.001, OR: 4.176; 95% CI: 2.008–8.685), lymphovascular invasion (p = 0.043, OR: 1.912; 95% CI: 1.018–3.592), extrathyroidal extension (p = <0.001, OR: 3.983; 95% CI: 1.970–8.054), and lymph node metastasis (p = 0.009, OR: 2.301; 95% CI: 1.224–4.326). Follicular variant (p = 0.001, OR: 7.011; 95% CI: 2.690–18.268), encapsulated (p = 0.017, OR: 2.433; 95% CI: 1.161–5.100), and absent of extrathyroidal extension (p = 0.033, OR: 2.890; 95% CI: 1.052–7.940) were associated with RAS mutations. Conclusion A significant association between BRAF V600E mutation and high clinical stage, tall-cell variants, non-encapsulated morphology, lymphovascular invasion, extrathyroidal extension, and lymph node metastasis in PTC was observed. RAS mutations were associated with the follicular variant, encapsulated tumor, and no extrathyroidal extension. HRAS -mutated PTC frequently exhibited tumor multifocality.

Lymph Node Metastasis in Papillary Thyroid Carcinoma, A Study of BRAF V600E and TERT Promoter Mutations

“…According to the multivariate analysis, nodule size, microcalcifications, and BRAF V600E mutations were all independently related with LN metastasis [24]. In addition, a study in Indonesia by Harahap et al (2023) concluded that BRAF V600E was associated with LN metastasis in PTC patients. They reported a significant association between BRAF V600E mutation with advanced clinical stage, tall cell variant of PTC, lymphovascular invasion, non-encapsulated morphology, and extrathyroidal extension.…”

“…This is the first study at Dr. Cipto Mangunkusumo Hospital to investigate the TERT rs2853669 mutation and its association with the occurrence of LN metastases. Furthermore, this work builds on a recent study by Harahap et al (2023), which investigated the link between BRAF V600E mutation and clinicopathological characteristics of PTC. A prior study by Perdana et al linked BRAF mutation to the chance of thyroid nodule malignancy based on cytology results, however it used cytological samples from a fine-needle aspiration biopsy (FNAB) [32].…”

“…2 µL of PCR results were electrophoresed with 1% Tris-borate-EDTA (TBE) agarose. If a band appears then BRAF amplification is proven to be present [11].…”

Correlation between genetic alterations and clinicopathological features of papillary thyroid carcinomas

“…BRAF mutation was associated with a lower HT incidence, a higher capsular invasion rate, and CPTC, a result that is 30 Comparison of the clinicopathologic features of BRAF V600E -mutated PTC with those of RAS-mutated PTC showed that BRAF V600E mutation was significantly associated with a lower incidence of HT and a higher rate of thyroid capsular invasion, suggesting that PTC with BRAF V600E mutation tends to exhibit a more aggressive behavior, a finding that aligns with prior studies. 31,32 There are also conflicting findings in previous studies regarding the relationship between mutations and clinicopathological factors; for example, some meta-analyses reported associations between BRAF V600E mutation and factors such as tumor multifocality, thyroid capsular invasion, ETE, LNM, and advanced stage, 33,34 while another study found no association between BRAF mutations and any clinicopathological factors. 35 Alternatively, the same mutations, including BRAF V600E , may be associated with various clinicopathological factors in different studies.…”