PTEN 5aa突变对胶质瘤进展、转移和耐药性的影响

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The incidence of this primary tumor has increased for the past 30 years and the overall mortality rate remains high. Standard treatment for GBM consists of radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide. EGFR is one of the most mutated gene in GBM patients, thus EGFR inhibitors have been indicated for GBM treatment. But neither treatment has so far failed to deliver significant responses in GBM patients due to drug resistance and recurrence with the mechanisms largely unknown. Mutation or deletion of PTEN, a tumor suppressor gene, has been shown to be involved in drug resistance to GBM. In this study we found a new type of mutation of PTEN, a 5 amino acids insertion at the C2 domain. More interestingly, this mutation were only found in recurrent and metastatic tumors and tumors with this mutation tend to be more aggressive. Here we studied the effect of PTEN 5aa mutation on cell proliferation, metastasis and drug resistance of GBM cells. Different signal pathways will be analyzed to explore how PTEN 5aa affects tumor cell activities. The goal of this study is to find the mechanism of GBM recurrence and drug resistance caused by PTEN 5aa mutation and to establish the role of PTEN 5aa as molecular marker of GBM recurrence and drug resistance. Potential therapies will be discussed for GBM patients with this mutation.

胶质母细胞瘤是最常见也最具侵袭性的原发性脑部肿瘤。近年来，原发性恶性脑肿瘤发生率逐年递增，临床治疗上主要以TMZ和放疗的标准疗法为主。由于EGFR突变在胶质瘤中非常常见，EGFR抑制剂也作为靶向疗法用于临床，但目前的治疗效果很差，常出现复发和耐药的情况，其具体的机制尚未明确。研究提示肿瘤抑制基因PTEN在胶质瘤中缺失或者突变与肿瘤复发和耐药有关，我们的研究首次发现PTEN的一个新突变，即在PTEN的C2结构域出现5个氨基酸的插入（PTEN 5aa）。该突变仅出现于复发的转移瘤当中，并且含有该突变的肿瘤恶性度很高。因此本研究将探讨PTEN 5aa对肿瘤细胞增殖、转移及其耐药性的影响，并分析PTEN 5aa对PTEN蛋白自身及下游通路的影响。预期明确PTEN 5aa作为肿瘤复发或者药物治疗的标签作用，同时探索可能的靶向治疗方案。