Makino Yasuhide, Arakawa Yoshiki, Yoshioka Ema, Shofuda Tomoko, Minamiguchi Sachiko, Kawauchi Takeshi, Tanji Masahiro, Kanematsu Daisuke, Nonaka Masahiro, Okita Yoshiko, Kodama Yoshinori, Mano Masayuki, Hirose Takanori, Mineharu Yohei, Miyamoto Susumu, Kanemura Yonehiro
Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Japan.
BMC Cancer. 2021 Sep 15;21(1):1025. doi: 10.1186/s12885-021-08733-4.
Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas.
This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis.
RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology.
RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.
在胶质瘤中已发现异柠檬酸脱氢酶（IDH）和BRAF等驱动基因的突变。同时，p53、RB1以及丝裂原活化蛋白激酶（MAPK）和/或磷脂酰肌醇-3-激酶（PI3K）信号通路的失调参与了胶质母细胞瘤的分子发病机制。RAS家族基因通过激活RAF和PI3K来激活MAPK，从而促进细胞增殖。RAS突变是多种癌症中众所周知的驱动突变，但对其在胶质瘤中的意义了解不足。本研究的目的是揭示胶质瘤中RAS突变的频率和临床表型。
本研究分析了2006年5月至2017年10月期间在京都大学和大阪国立医院切除并保存为未固定或冷冻标本的242例胶质瘤中的RAS突变及其临床意义。采用桑格测序法分析IDH1/2、H3F3A、HIST1H3B和端粒酶逆转录酶（TERT）启动子的热点突变以及KRAS、HRAS和NRAS的第2外显子和第3外显子，并采用多重连接依赖探针扩增法分析1p/19q共缺失。对部分RAS突变肿瘤进行DNA甲基化阵列分析以提高诊断准确性。
在4例胶质瘤中发现RAS突变，其中1例间变性少突胶质细胞瘤、2例间变性星形细胞瘤（均为IDH野生型）和1例节细胞胶质瘤中分别有3例KRAS突变和1例NRAS突变。RAS突变型胶质瘤具有多种胶质瘤组织学类型。
RAS突变似乎不常见，且与胶质瘤的任何特定组织学表型均无关联。
