Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas
Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas
复制标题
DOI：
10.1007/s00401-014-1247-5
复制
发表时间：
2014-06-01
影响因子：
12.7
通讯作者：
Ichimura, Koichi
中科院分区：
文献类型：
--
作者：
Fukushima, Shintaro;Otsuka, Ayaka;Ichimura, Koichi
颅内生殖细胞肿瘤（iGCT）是日本15岁以下儿童中第二常见的脑肿瘤。iGCT的发病机制在很大程度上尚未探索。尽管已知iGCT的一个子集具有KIT突变，但其对生物学和患者生存的影响尚未确定。在这项研究中，我们研究了参与KIT信号通路的基因。通过直接测序对65例iGCT（30例纯生殖细胞瘤、14例畸胎瘤、18例混合型GCT、2例卵黄囊瘤、1例绒毛膜癌）进行KIT、KRAS、NRAS、HRAS、BRAF、PDGFRA和IDH 1突变筛查。免疫组化和定量PCR检测KIT表达。通过阵列比较基因组杂交（aCGH）分析染色体状态。仅在KIT和RAS中检测到体细胞突变，这在纯生殖细胞瘤中常见（60.0%），但在非生殖细胞瘤性GCT（NGGCT）中罕见（8.6%）。所有KIT/RAS突变都是相互排斥的。无论突变状态或mRNA表达，KIT蛋白在所有生殖细胞瘤中表达，而仅在54.3%的NGGCT中表达。aCGH检测1例单纯生殖细胞瘤中KIT扩增。在单纯性生殖细胞瘤中，KIT mRNA的高表达与KIT/RAS改变和严重的染色体不稳定性相关。我们的研究结果表明，KIT信号通路的改变在生殖细胞瘤的发展中起着重要的作用。纯生殖细胞瘤可能通过两种不同的发病机制发展：一种是KIT/RAS改变，KIT mRNA表达升高和严重的染色体不稳定性，另一种是通过一种尚未确定的机制，而没有任何上述异常。
Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 15 in Japan. The pathogenesis of iGCTs is largely unexplored. Although a subset of iGCTs is known to have KIT mutation, its impact on the biology and patients' survival has not been established. In this study, we investigated genes involved in the KIT signaling pathway. 65 iGCTs (30 pure germinomas, 14 teratomas, 18 mixed GCTs, 2 yolk sac tumors, 1 choriocarcinoma) were screened for mutation of KIT, KRAS, NRAS, HRAS, BRAF, PDGFRA, and IDH1 by direct sequencing. KIT expression was examined by immunohistochemistry and quantitative PCR. Chromosomal status was analyzed by array-comparative genomic hybridization (aCGH). Somatic mutations were detected only in KIT and RAS, which were frequently observed in pure germinomas (60.0 %), but rare in non-germinomatous GCTs (NGGCTs) (8.6 %). All KIT/RAS mutations were mutually exclusive. Regardless of the mutation status or mRNA expression, the KIT protein was expressed in all germinomas, while only in 54.3 % of NGGCTs. Amplification of KIT was found in one pure germinoma by aCGH. In pure germinomas, high expression of KIT mRNA was associated with the presence of KIT/RAS alterations and severe chromosomal instability. Our results indicate that alterations of the KIT signaling pathway play an important role in the development of germinomas. Pure germinomas may develop through two distinct pathogeneses: one with KIT/RAS alterations, elevated KIT mRNA expression and severe chromosomal instability, and the other through yet an unidentified mechanism without any of the above abnormalities.