BRAF and TERT promoter mutations in the aggressiveness of papillary thyroid carcinoma: a study of 653 patients.

Langping Jin,Siyang Dong,Yili Zhou,Fan Yang,Ouchen Wang,Yehuan Liu,Endong Chen,Ruichao Zeng,Weili Wu,Xiaohua Zhang,Xiangjian Zhang,Yefeng Cai,Chuanmeng Pan,Mingzhao Xing

doi:10.18632/oncotarget.7811

Abstract

The role of telomerase reverse transcriptase (TERT) gene promoter mutations in the aggressiveness of papillary thyroid cancer (PTC) remains to be further investigated. Here we examined the relationship of TERT promoter mutations and BRAF V600E with the clinicopathological features of PTC in 653 patients. Sanger sequencing of genomic DNA from primary PTC tumors was performed for mutation detection and genotype-clinicopathological correlation of the tumor was analyzed. BRAF V600E and TERT promoter mutations were found in 63.7% (416 of 653) and 4.1% (27 of 653) of patients, respectively; the latter became 9.8% when only tumors ≥ 1.5 cm were analyzed. TERT promoter mutations occurred more frequently in BRAF mutation-positive cases compared to wild-type cases, being 5.3% in the former versus 2.1% in the latter (P = 0.050). BRAF and TERT promoter mutations were each significantly associated with high-risk clinicopathological features of PTC, such as old patient age, large tumor size, extrathyroidal invasion, capsular invasion, and advanced disease stages. Coexistence of BRAF V600E and TERT promoter mutations was particularly associated with high-risk clinicopathological features, as exemplified by extrathyroidal invasion seen in 54.5% (12/22) of patients harboring both mutations versus 9.9% (23/232) of patients harboring neither mutation (P < 0.001). Thus, this study, the largest on TERT mutation so far, demonstrates a significant role of BRAF V600E and TERT promoter mutations in the aggressiveness of PTC, which is particularly robust and cooperative when the two mutations coexist. These results, together with previous studies, establish a significant role of these mutations in the aggressiveness of PTC.

Highlights

Papillary thyroid cancer (PTC) is the most common endocrine malignancy, which constitutes the primary component of the rapid rise in the incidence of thyroid cancer widely seen in recent decades [1, 2]
We demonstrated a significant role of BRAF V600E mutation in the development of aggressive features of PTC, confirming the findings in some previous studies
Our study found an interesting inverse association between the BRAF V600E mutation and Hashimoto’s thyroiditis (HT); the prevalence of BRAF mutation in PTC was significantly lower in patients with coexisting HT compared with those without HT

Summary

Introduction

Papillary thyroid cancer (PTC) is the most common endocrine malignancy, which constitutes the primary component of the rapid rise in the incidence of thyroid cancer widely seen in recent decades [1, 2]. Given this heterogeneity of the disease prognosis, it is often debatable on how to appropriately manage individual cases of PTC when the goal is to optimize the balance between aggressively treating the cancer to prevent disease recurrence and patient mortality and conservatively limiting the treatment extent to reduce the risk www.impactjournals.com/oncotarget of treatment-associated complications [2,3,4] To overcome this challenge will rely on improved risk stratifications to more accurately identify the patients who most likely have a poor prognosis.

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