Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population

Abstract

Context.-Papillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. A limited number of studies have examined genetic mutations affecting the mitogen-activated protein kinase (MAPK) pathway in the pediatric population.Objective.-To examine mutations affecting this pathway in PTC in our pediatric population and compare the BRAF V600E mutation rates in pediatric and adult tumors.Design.-Eighty-four patients, including 14 pediatric and 70 adult, with PTC were tested for the BRAF V600E mutation by using real-time polymerase chain reaction and sequencing. Additionally, we examined the rate of RAS point mutations with real-time polymerase chain reaction and rearrangements of RET/PTC1 and RET/PTC3 in the pediatric group with fluorescence in situ hybridization. Clinical and histologic data were compared as well.Results.-Of 77 tumors that had an interpretable result, the BRAF V600E mutant was identified in 4 of 13 pediatric patients (31%) and 43 of 64 adult patients (67%), which was a significant difference (using Fisher exact test, P ¼ .03). One pediatric and 6 adult cases did not reveal an interpretable result with melting curve analysis. One of these cases harbored a rare 3-base pair deletion mutation (c.1799_1801delTGA). Mutations in RAS genes were not seen in any pediatric tumors. One tumor with a RET/PTC1 rearrangement and another with RET/PTC3 were identified in the pediatric population (15%).Conclusions.-The rate of the BRAF V600E mutation in the pediatric population is significantly lower than that seen in the adult population. Mutations in RAS do not contribute significantly to pediatric PTC. This experience from our institution adds to the growing body of knowledge regarding tumor genetics in pediatric PTC.(Arch Pathol Lab Med. 2016;140:134-139; doi: 10.5858/ arpa.2014-0612-OA) P apillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. Despite having an excellent prognosis with long-term mortality rates of less than 1%, 1,2 pediatric patients with PTC tend to present with advanced disease often with increased rates of extrathyroidal tumor extension, lymphovascular invasion, and distant metastases. 1,3-5The distinct clinical nature of papillary thyroid cancer in the pediatric population has prompted interest in the molecular tumorigenesis. The mitogen-activated protein kinase (MAPK) pathway includes components of particular interest, including BRAF, RAS, and RET. Between 37% and 52% of PTCs have been linked to the specific BRAF mutation V600E, and clinical correlations support that this foretells a more aggressive disease course in adults. [6][7][8][9] The incidence of this BRAF mutation in the pediatric population is thought to be lower than in adults with rates of 0% to 37%, 10-15 though 1 recent series 16 revealed a rate of 63%. The rearrangement mutations of RET are also considered a major contributor to PTC tumorigenesis, but rates of this mutation have fluctuated widely in reported series.17 RET/PTC rearrangements have been associated with young age 18 an...

Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions

“…Consistent with previous retrospective studies , we recognized a relative paucity of BRAF V600E mutations in our series of PAYA PTC cases compared with the full cohort of patients of any age (46% vs. 70%) and identified a higher percentage of oncogenic fusions in the younger subpopulation (37% vs. 15%). Among PAYA patients with PTC, oncogenic BRAF mutations and kinase fusions were detected in 86% of cases.…”

“…Several studies have genomically characterized pediatric thyroid carcinomas, most frequently in the context of radiation exposure . Genomic rearrangements have been reported to be more prevalent in pediatric patients with radiation‐induced PTC than in pediatric patients with sporadic PTC .…”

AGK‐BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma

“…On the other hand, some of the most common genetic alterations of adult PTC are rare or absent in pediatric PTC, supporting the hypothesis that biological features of PTC may differ by patient age . For instance, BRAF V600E mutation represents the most prevalent event in PTC reported in adults (23–63%) but the prevalence is lower (3–48%) in pediatric PTC patients in most studies . BRAF fusion has rarely been reported in adult PTC, whereas it has been described in radiation‐exposed pediatric PTC .…”

“…Despite the vast number of studies conducted in adults, there is limited information regarding the prevalence and clinical significance of BRAF V600E in pediatric PTC. 13,14,20,22,[28][29][30][31][32][33][34][35]45,46 In fact, a significantly lower percentage of the pediatric cases (≤18 years old) had BRAF V600E mutation ( Table 2), suggesting that other less common or noncanonical mutation in BRAF gene could serve as surrogates for the BRAF V600E canonical mutation or even that BRAF is not essential for development pediatric PTC and diverse pathogenic mechanisms may be involved.…”

“…12,14,[22][23][24][25][26] For instance, BRAF V600E mutation represents the most prevalent event in PTC reported in adults (23-63%) but the prevalence is lower (3-48%) in pediatric PTC patients in most studies. 12,14,[27][28][29][30][31][32][33][34][35] BRAF fusion has rarely been reported in adult PTC, whereas it has been described in radiation-exposed pediatric PTC. 13,[36][37][38] The most prevalent BRAF fusions reported in radiation-exposed pediatric PTC are AKAP9-BRAF and AGK-BRAF.…”