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

儿童甲状腺乳头状癌中BRAF和MAPK通路中其他相关基因的突变

Gertz RJ,Nikiforov Y,Rehrauer W,McDaniel L,Lloyd RV

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 = .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.

摘要

背景:儿童甲状腺乳头状癌比较少见。少数研究对儿童甲状腺乳头状癌中影响促分裂原活化蛋白激酶(MAPK)通路相关的基因突变进行了检测。

目的:检测儿童甲状腺乳头状癌中MAPK通路相关的基因突变,并比较儿童和成人甲状腺乳头状癌中BRAF V600E突变率。

方法:用real-time PCR和测序方法检测14例儿童、70例成人甲状腺乳头状癌中BRAF V600E突变情况。此外,对14例儿童甲状腺乳头状癌用real-time PCR检测RAS点突变率,荧光原位杂交方法检测RET/PTC1 和RET/PTC3基因重排。同时对临床病理学特征进行比较分析。

结果:84例甲状腺乳头状癌中有77例得到了满意的结果,溶解曲线分析中1例儿童和6例成人没有显示有意义的结果。儿童甲状腺乳头状癌BRAF V600E突变率与成人相比[31%(4/13)VS 67%(43/64)],差异具有统计学意义(Fisher确切概率法, P = 0.03)。77例中有1例存在罕见的3个碱基对缺失突变(c.1799_1801delTGA)。儿童甲状腺乳头状癌中无RAS基因突变,1例RET/PTC1基因重排,15%病例存在RET/PTC3基因重排。

结论:儿童甲状腺乳头状癌BRAF V600E突变率明显低于成人甲状腺乳头状癌。儿童甲状腺乳头状癌RAS基因突变无临床意义。本实验积累了一些儿童甲状腺乳头状癌遗传学方面的经验。

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