Neuro Oncol：脑瘤中过多基因突变或许并不是件坏事儿

  DNA突变可以引发癌症，但在很多情况下，过多的突变或许意味着患者预后良好；近日，刊登在国际杂志Neuro-Oncology上的一篇研究报道中，来自耶鲁大学的研究人员通过对700多份脑部肿瘤的样本进行基因组学分析揭示了一种名为胶质母细胞瘤（GBM）的恶性脑部肿瘤的特殊亚型，这种亚型肿瘤拥有成千上万种肿瘤特异性的DNA错误或突变，而其却和病人存活期长直接相关。
  研究者Murat Gunel表示，这就为我们后期开发新型个体化疗法来治疗许多恶性脑瘤提供了新的希望；目前我们已经可以利用多种互补切割的前沿基因组学技术来应用于临床中分析个体的癌症，而且我们也理解了癌症的分子组成，并为揭示特殊的癌症致命点以开发新型精确疗法提供了帮助。
  研究者在这种新型胶质母细胞瘤亚型中发现多达10000个突变，而较为典型的肿瘤所包含的突变不足100个；一般理论认为携带大量突变的细胞会诱发机体对癌细胞产生攻击性的免疫反应，而携带少量突变的细胞则会逃避这种免疫检测。尽管研究者所发现的这种胶质母细胞瘤亚型较少，然而在某些时候利用标准化的化疗方法或许也会引发产生高突变的肿瘤，的确，被用作治疗胶质母细胞瘤的药物替莫唑胺曾经就被认为可以增加肿瘤的突变。
  Gunel指出，或许机体天生的免疫系统并不足以强大来消除脑部肿瘤中的癌细胞，然而如果可以开发出一种名为检查点抑制剂的新一代化疗药物，或许就可以用于进行高突变肿瘤的治疗，或许更多的癌细胞就可以被靶向摧毁；当前研究者正在进行临床试验，他们希望通过理解病人个体肿瘤的分子遗传组成或许可以帮助改善临床试验及后期疗法的开发。（转化医学网360zhyx.com）
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Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis
Neuro Oncol    doi: 10.1093/neuonc/nov027
E. Zeynep Erson-Omay†, Ahmet Okay Çağlayan†, Nikolaus Schultz, Nils Weinhold, S. Bülent Omay, Koray Özduman, Yavuz Köksal, Jie Li, Akdes Serin Harmancı, Victoria Clark, Geneive Carrión-Grant, Jacob Baranoski, Caner Çağlar, Tanyeri Barak, Süleyman Coşkun, Burçin Baran, Doğan Köse, Jia Sun, Mehmet Bakırcıoğlu, Jennifer Moliterno Günel, M. Necmettin Pamir, Ketu Mishra-Gorur, Kaya Bilguvar, Katsuhito Yasuno, Alexander Vortmeyer, Anita J. Huttner, Chris Sander and Murat Günel
Background Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis.

Methods We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features.

Results We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these “ultramutated” tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival.

Conclusions We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.