Jones DeAnalisa C, Scanteianu Adriana, DiStefano Matthew, Bouhaddou Mehdi, Birtwistle Marc R
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
PLoS One. 2018 Jan 17;13(1):e0190664. doi: 10.1371/journal.pone.0190664. eCollection 2018.
Current treatments for glioblastoma multiforme (GBM)-an aggressive form of brain cancer-are minimally effective and yield a median survival of 14.6 months and a two-year survival rate of 30%. Given the severity of GBM and the limitations of its treatment, there is a need for the discovery of novel drug targets for GBM and more personalized treatment approaches based on the characteristics of an individual's tumor. Most receptor tyrosine kinases-such as EGFR-act as oncogenes, but publicly available data from the Cancer Cell Line Encyclopedia (CCLE) indicates copy number loss in the ERBB4 RTK gene across dozens of GBM cell lines, suggesting a potential tumor suppressor role. This loss is mutually exclusive with loss of its cognate ligand NRG1 in CCLE as well, more strongly suggesting a functional role. The availability of higher resolution copy number data from clinical GBM patients in The Cancer Genome Atlas (TCGA) revealed that a region in Intron 1 of the ERBB4 gene was deleted in 69.1% of tumor samples harboring ERBB4 copy number loss; however, it was also found to be deleted in the matched normal tissue samples from these GBM patients (n = 81). Using the DECIPHER Genome Browser, we also discovered that this mutation occurs at approximately the same frequency in the general population as it does in the disease population. We conclude from these results that this loss in Intron 1 of the ERBB4 gene is neither a de novo driver mutation nor a predisposing factor to GBM, despite the indications from CCLE. A biological role of this significantly occurring genetic alteration is still unknown. While this is a negative result, the broader conclusion is that while copy number data from large cell line-based data repositories may yield compelling hypotheses, careful follow up with higher resolution copy number assays, patient data, and general population analyses are essential to codify initial hypotheses prior to investing experimental resources.
多形性胶质母细胞瘤（GBM）是一种侵袭性脑癌，目前的治疗效果甚微，中位生存期为14.6个月，两年生存率为30%。鉴于GBM的严重性及其治疗的局限性，需要发现GBM的新药物靶点，并基于个体肿瘤特征制定更个性化的治疗方法。大多数受体酪氨酸激酶，如表皮生长因子受体（EGFR），发挥癌基因的作用，但来自癌症细胞系百科全书（CCLE）的公开数据表明，在数十种GBM细胞系中，ERBB4受体酪氨酸激酶（RTK）基因存在拷贝数缺失，提示其可能具有肿瘤抑制作用。在CCLE中，这种缺失与它的同源配体神经调节蛋白1（NRG1）的缺失也是相互排斥的，这更有力地表明了其功能作用。癌症基因组图谱（TCGA）中临床GBM患者的高分辨率拷贝数数据显示，在69.1%携带ERBB4拷贝数缺失的肿瘤样本中，ERBB4基因第1内含子区域被删除；然而，在这些GBM患者（n = 81）匹配的正常组织样本中也发现该区域被删除。使用DECIPHER基因组浏览器，我们还发现这种突变在普通人群中的发生频率与在疾病人群中的发生频率大致相同。从这些结果我们得出结论，尽管CCLE有相关提示，但ERBB4基因第1内含子的这种缺失既不是新生驱动突变，也不是GBM的易感因素。这种显著发生的基因改变的生物学作用仍然未知。虽然这是一个负面结果，但更广泛的结论是，虽然基于大型细胞系数据存储库的拷贝数数据可能产生令人信服的假设，但在投入实验资源之前，通过更高分辨率的拷贝数检测、患者数据和普通人群分析进行仔细的后续研究对于验证初始假设至关重要。
