Relevance and clinicopathologic relationship of BRAF V600E, TERT and NRAS mutations for papillary thyroid carcinoma patients in Northwest China

Abstract

Background: To determine the relevance of the single or combination mutations of BRAF V600E, TERT, and NRAS genes and the clinicopathologic relationship in papillary thyroid cancer (PTC). Methods: Patients with PTC were enrolled into the study between February 2018 and April 2019. Based on the number of mutant genes, we classified the participants into single BRAF V600E mutation group, double mutations group and no mutation group. Single factor and multiple logistic regression analyses were applied to explore the independent factors. Review Manager 5.3 was used for meta-analysis to review the clinical efficacy of gene co-mutations. Results: Finally, 483 patients were enrolled into the study and 419 (86.7%) of them harbored BRAF V600E mutation. TERT or NRAS mutation was likely to coexist with BRAF V600E mutation in PTC. BRAF V600E and NRAS promoter co-mutations was identified in 6 patients, with a prevalence of 1.2%. Prevalence of BRAF V600E and TERT coexistence in PTC was 2.1%. Significant differences were found among age, pathology, multifocality, bilateral lesions, lymph node metastasis, and 131I radiotherapy, P < 0.01. Multiple logistic regression analyses demonstrated that age [odds ratio (OR) = 1.044, 95% confidence interval (CI) = 1.013-1.076; P = 0.006], lymph node metastasis [OR = 0.094, 95% CI = 0.034-0.264; P < 0.001], 131I radiotherapy [OR = 7.628, 95% CI = 2.721-21.378; P < 0.001] were risk factors for BRAF V600E mutation. Besides, age [OR = 1.135, 95% CI = 1.069-1.205; P < 0.001], multiple leisions [OR = 4.128, 95% CI = 1.026-16.614; P = 0.046], pathology [OR = 3.954, 95% CI = 1.235-12.654; P = 0.021] were independent factors for combination mutations. Meta-analysis showed significant association of BRAF V600E+/TERT+ co-mutations with lymph node metastasis, multifocality, distant metastasis, tumor recurrence, extrathyroidal extension, and dead of disease. Conclusions: Prevalence of BRAF V600E mutation in Northwest China was higher than other areas. Age, multiple lesions, and pathology were independent factors for double mutation of BRAF V600E/TERT or BRAF V600E/NRAS. Coexistence of BRAF V600E and TERT promoter mutations was significantly correlated with poor outcome.

Genomic characterization of high-recurrence risk papillary thyroid carcinoma in a southern Chinese population

“…Xing et al reported that RAS mutation alone does not indicate malignancy in thyroid tumors [26]. However, thyroid cancer with dual mutations of RAS with BRAF V600E or TERT was associated with worse clinicopathologic outcomes [11,27]. In our current study, dual mutations of RAS and BRAF V600E were only seen in multifocal PTC (p = 0.015).…”

“…RAS and BRAF V600E dual mutations were also seen in this patient cohort and were associated with multifocal disease. In general, RAS and BRAF V600E mutations tend to be mutually exclusive, however, there have been reports of their coexistence in PTC [11,28]. Whether their…”

“…As thyroid cancer incidence has increased rapidly in China in recent years, and targeted therapies have become available in China to treat various types of cancer [11], we set out to characterize the genetic mutations of PTC in a high-recurrent risk cohort from Southern China to better understand the genetic-clinicopathologic correlation of this disease andprovide insight into the target therapy options.…”

PIWI-interacting RNAs piR-13643 and piR-21238 are promising diagnostic biomarkers of papillary thyroid carcinoma

“…A search of the TCGA-THCA database identified and characterized > 96% of driver mutations of PTC, finding BRAF (mutation in 59.7% PTC), NRAS (mutation in 8.5% PTC) and HRAS (mutation in 3.5% PTC) as the most common causative genes [33,34]. Our data are consistent with previous studies confirming that BRAF V600E gene mutation is important in the diagnosis of PTC [35][36][37]. However, BRAF also has been reported to mutate in benign thyroid nodules and is not suitable for early diagnosis of thyroid cancer [30,38,39].…”

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

“…The most common oncogenic duet that has been investigated for its association with aggressive thyroid cancer phenotype is BRAF V600E and mutated TERT promoter. The presence of TERT promoter mutations in synergy with BRAF mutations has been associated with aggressive thyroid tumor characteristics, which include lymph node metastasis, distant metastasis, tumor recurrence, multifocality, extrathyroidal extension, and patient mortality [74][75][76][77]. The two parts of this oncogenic duet (BRAF V600E and mutated TERT promoter) have been shown to work cooperatively together to promote oncogenesis, leading to aggressive thyroid cancer phenotype [78].…”