High Rate of BRAF and RET/PTC Dual Mutations Associated with Recurrent Papillary Thyroid Carcinoma

Abstract

Purpose: Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, usually possesses BRAF mutation or rearranged in translation (RET)/PTC rearrangements. PTC usually possesses BRAF mutation or RET/PTC rearrangements. The mutation status of patients with recurrent PTC has never been characterized in a large population. Experimental Design: Mutation status was determined in a cohort of 54 patients with recurrent PTC and analyzed for clinicopathologic relationships. BRAF and ras mutations were determined by PCR and sequencing of genomic DNA. RET/PTC rearrangements were analyzed by reverse transcription-PCR. Results: BRAF mutation in exon 15 (V600E) was found in 42/54 (77.8%) recurrent PTC patients. The RET/PTC rearrangements were detected in 9 of 54 (16.7%) patients. In addition, 5 of 54 (9.3%) recurrent PTC patients had both a BRAF mutation and a RET/PTC rearrangement. The prevalence of tumors with dual mutations found in the recurrent population far exceeds the frequency historically reported for patients with primary PTC. Patients with dual mutations were significantly older (80% older than 45 years) than patients with a BRAF mutation alone (38% older than 45 years). Conclusions: Recurrent PTC is significantly associated with a predominant BRAF mutation. RET/PTC rearrangements, although commonly associated with primary PTCs in younger patients, are uncommonly found in recurrent PTC patients. In addition, the incidence of dual mutations was higher in patients with recurrent PTC than in those primary PTC, as reported by others.Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy accounting for 70% to 80% of thyroid cancer cases (1). In most cases, PTC has a very good prognosis, particularly in patients younger than ages 45 years at the time of diagnosis. However, roughly 5.7% of patients at 5 years and 9.4% of patients at 10 years with primary PTC will experience a recurrence of tumor (2). Recurrence typically occurs in the neck region, either in lymph nodes or in the thyroid bed, and less commonly in distance sites such as lung or bone. Patients who were older than 45 years at the time of initial diagnosis have a much worse prognosis when the cancer recurs. The 15-year mortality rate for this group is f30% for patients with local recurrence in the neck, and roughly 50% for patients with recurrence at distance sites (1,3,4).Several types of genetic alterations have been found in primary PTC, including mutations in BRAF or ras, and rearrangements of the RET or NTRK1 tyrosine kinase receptor. The incidence of BRAF mutations ranges from 29% to 83% depending on the cohort studied (5). The most common type of BRAF mutation found in primary PTC is a T to A substitution at nucleotide 1799 in exon 15, which results in conversion of a valine to glutamic acid at codon 600 (V600E) of the BRAF protein (6, 7). BRAF mutation has been associated with poor prognosis in PTC patients (8-10). The incidence of RET/PTC rearrangements in PTC ranges from 2.5% to 67.0% depending on the coh...

Efficient detection of the V600E mutation of the BRAF gene in papillary thyroid carcinoma using multiplex allele-specific polymerase chain reaction combined with denaturing high-performance liquid chromatography

“…Recently, Alzahrani and Xing (2013) also found that BRAF gene mutations in thyroid cancer could predict lymph node metastasis, which is consistent with our results. Furthermore, multivariate regression analysis also suggested that lymph node metastasis and the presence of BRAF V600E mutations were independent predictors for tumor prognosis, which is also in agreement with the literature (Costa et al, 2008;Henderson et al, 2009). As BRAF gene mutations and lymph node metastasis are closely associated with tumor recurrence, pre-operative detection of the mutation and conventional lymph node dissection may help to reduce the recurrence rate (Bozec et al, 2011;Alzahrani and Xing, 2013).…”

“…Although several studies have found that BRAF gene mutations are closely correlated with thyroid cancer prognosis, few of these studies have come from China (Costa et al, 2008;Gong et al, 2009;Henderson et al, 2009;Xing et al, 2009;Howell et al, 2011). In the present study, we demonstrated that the BRAF V600E mutation is closely related with age, tumor staging, and clinical prognosis.…”

Recurrent Differentiated Thyroid Cancer

“…Both mutations were simultaneously present in 9.3% of patients with recurrent disease, a much higher percentage than the prevalence of dual mutations in primary disease. These findings support the idea that BRAF mutations, as well as dual mutations, are significantly associated with recurrent papillary thyroid carcinoma [23]. A BRAF V600E mutation in patients older than 65 with papillary thyroid cancer has been associated with a higher incidence of recurrence than in younger patients (10% and 2%, respectively).…”

Clinical Responses to Vemurafenib in Patients with Metastatic Papillary Thyroid Cancer Harboring BRAFV600EMutation

“…Among several known genetic aberrations of PTC, kinaseactivating mutations in the V-raf murine sarcoma viral oncogene homolog B1 (BRAF) proto-oncogene are the most frequent event, found in nearly half of all PTCs, and the incidence rate of these mutations approaches 80% in recurrent or metastatic PTCs (13)(14)(15). A single amino acid substitution, from valine to glutamic acid at codon 600 (V600E), accounts for approximately 90% of all BRAF mutations (13)(14)(15)(16).…”