Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma
Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma
复制标题
DOI：
10.1007/s00401-011-0802-6
复制
发表时间：
2011-03-01
影响因子：
12.7
通讯作者：
von Deimling, Andreas
中科院分区：
文献类型：
--
作者：
Schindler, Genevieve;Capper, David;von Deimling, Andreas
V600E类型的错义突变构成了v-RAF小鼠肉瘤病毒癌基因同源B1(BRAF)基因中绝大多数与肿瘤相关的体细胞变化。这些变化最初在黑色素瘤、结肠癌和乳头状甲状腺癌中被描述，在原发性神经系统肿瘤中也观察到了这些变化，尽管频率很低。我们用直接测序的方法分析了1320例成人和儿童神经系统肿瘤的BRAF基因第15外显子，这些肿瘤包括不同类型的神经胶质、胚胎、神经元和神经胶质细胞肿瘤、脑膜肿瘤、腺垂体/鞍区肿瘤和周围神经系统肿瘤。共检测到96个BRAF突变，其中93个为V600E型，3个在密码子599和600之间有三个碱基对插入。BRAF(V600E)突变频率最高的是WHO II级多形性黄色星形细胞瘤(42/；66%)和伴间变的多形性黄色星形细胞瘤(15/23；65%)，以及WHO I级节细胞胶质瘤(14/77，18%)、WHO III级间变性节细胞胶质瘤(3/6)和毛细胞性星形细胞瘤(9/97，9%)。在毛细胞性星形细胞瘤中，BRAF(V600E)突变与小脑外部位密切相关(p=0.009)，在间脑肿瘤中最常见(4/12；33%)。胶质母细胞瘤和其他胶质瘤的特点是突变频率低或没有突变。在胚胎肿瘤、脑膜瘤、神经鞘肿瘤和垂体腺瘤等非胶质细胞肿瘤中未检测到突变。多形性黄色星形细胞瘤、神经节细胞胶质瘤和小脑外毛细胞性星形细胞瘤的高突变频率意味着BRAF(V600E)突变是这些罕见肿瘤的有价值的诊断标记。未来的临床试验应该解决BRAF(V600E)突变的脑瘤患者是否将从BRAF(V600E)导向的靶向治疗中受益。
Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF (V600E) mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF (V600E) mutation was strongly associated with extra-cerebellar location (p = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF (V600E) mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF (V600E) mutant brain tumor patients will benefit from BRAF (V600E)-directed targeted therapies.