Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Washington University School of Medicine, St. Louis, MO 63110, USA.
Genes (Basel). 2020 May 1;11(5):499. doi: 10.3390/genes11050499.
Sarcomas are highly aggressive cancers that have a high propensity for metastasis, fail to respond to conventional therapies, and carry a poor 5-year survival rate. This is particularly true for patients with neurofibromatosis type 1 (NF1), in which 8%-13% of affected individuals will develop a malignant peripheral nerve sheath tumor (MPNST). Despite continued research, no effective therapies have emerged from recent clinical trials based on preclinical work. One explanation for these failures could be the lack of attention to intra-tumoral heterogeneity. Prior studies have relied on a single sample from these tumors, which may not be representative of all subclones present within the tumor. In the current study, samples were taken from three distinct areas within a single tumor from a patient with an NF1-MPNST. Whole exome sequencing, RNA sequencing, and copy number analysis were performed on each sample. A blood sample was obtained as a germline DNA control. Distinct mutational signatures were identified in different areas of the tumor as well as significant differences in gene expression among the spatially distinct areas, leading to an understanding of the clonal evolution within this patient. These data suggest that multi-regional sampling may be important for driver gene identification and biomarker development in the future.
肉瘤是高度侵袭性的癌症，具有高度转移倾向，对常规疗法无反应，5 年生存率低。这在 1 型神经纤维瘤病（NF1）患者中尤为如此，其中 8%-13%的受影响个体将发展为恶性外周神经鞘瘤（MPNST）。尽管持续进行研究，但最近基于临床前工作的临床试验并未出现有效的治疗方法。这些失败的一个解释可能是缺乏对肿瘤内异质性的关注。先前的研究依赖于这些肿瘤的单个样本，这些样本可能不能代表肿瘤内存在的所有亚克隆。在当前的研究中，从 NF1-MPNST 患者的单个肿瘤中三个不同区域采集了样本。对每个样本进行了全外显子组测序、RNA 测序和拷贝数分析。还获得了一份血液样本作为种系 DNA 对照。在肿瘤的不同区域中鉴定出了不同的突变特征，以及在空间上不同的区域之间存在显著的基因表达差异，从而了解了该患者内的克隆进化。这些数据表明，多区域采样对于未来驱动基因鉴定和生物标志物开发可能很重要。
