Goode Benjamin, Mondal Gourish, Hyun Michael, Ruiz Diego Garrido, Lin Yu-Hsiu, Van Ziffle Jessica, Joseph Nancy M, Onodera Courtney, Talevich Eric, Grenert James P, Hewedi Iman H, Snuderl Matija, Brat Daniel J, Kleinschmidt-DeMasters Bette K, Rodriguez Fausto J, Louis David N, Yong William H, Lopes M Beatriz, Rosenblum Marc K, Butowski Nicholas, Tihan Tarik, Bollen Andrew W, Phillips Joanna J, Wiita Arun P, Yeh Iwei, Jacobson Matthew P, Bastian Boris C, Perry Arie, Solomon David A
Department of Pathology, University of California, San Francisco, CA, 94143, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, 94158, USA.
Nat Commun. 2018 Feb 23;9(1):810. doi: 10.1038/s41467-018-02826-8.
Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.
脊索样胶质瘤是一种罕见的脑肿瘤，被认为起源于第三脑室前壁终板的特殊胶质细胞。尽管在组织学上为低级别，但脊索样胶质瘤通常预后较差，因为它们在第三脑室的典型位置使得切除具有挑战性，且尚未开发出有效的辅助治疗方法。在此，我们对13例脊索样胶质瘤进行了基因组分析，在所有肿瘤中均鉴定出PRKCA基因存在反复出现的D463H错义突变，该突变位于编码蛋白激酶Cα（PKCα）的激酶结构域。在永生化的人星形胶质细胞中表达突变型PRKCA会导致磷酸化ERK增加和不依赖贴壁的生长，而MEK抑制可阻断这种生长。这些研究将PRKCA定义为人类癌症中反复突变的癌基因，并确定了这种罕见脑肿瘤潜在的治疗弱点。
