Erson-Omay E Zeynep, Çağlayan Ahmet Okay, Schultz Nikolaus, Weinhold Nils, Omay S Bülent, Özduman Koray, Köksal Yavuz, Li Jie, Serin Harmancı Akdes, Clark Victoria, Carrión-Grant Geneive, Baranoski Jacob, Çağlar Caner, Barak Tanyeri, Coşkun Süleyman, Baran Burçin, Köse Doğan, Sun Jia, Bakırcıoğlu Mehmet, Moliterno Günel Jennifer, Pamir M Necmettin, Mishra-Gorur Ketu, Bilguvar Kaya, Yasuno Katsuhito, Vortmeyer Alexander, Huttner Anita J, Sander Chris, Günel Murat
Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut (E.Z.E.-O., A.O.Ç., S.B.O., A.S.H., V.C., G.C.-G., J.B., C.Ç., T.B., S.C., B.B., M.B., J.M.G., K.M.-G., K.B., K.Y., M.G.); Department of Genetics, Yale School of Medicine, New Haven, Connecticut (K.B., M.G.); Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York (N.S., N.W., C.S.); Department of Neurosurgery, Acıbadem University School of Medicine, Istanbul, Turkey (K.O., M.N.P.); Division of Hematology and Oncology, Faculty of Medicine, Department of Pediatrics, Selçuk University, Konya, Turkey (Y.K., D.K.); Department of Pathology, Yale School of Medicine, New Haven, Connecticut (J.L., J.S., A.V., A.J.H.).
Neuro Oncol. 2015 Oct;17(10):1356-64. doi: 10.1093/neuonc/nov027. Epub 2015 Mar 3.
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.
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.
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.
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.
恶性高级别胶质瘤（HGGs），包括最具侵袭性的多形性胶质母细胞瘤，表现出显著的临床和基因组异质性。尽管最近取得了进展，但HGGs的总体生存率及其对治疗的反应仍然很差。为了通过将基因组格局与临床行为相关联，从而进一步深入了解疾病病理生理学，进而识别与预后改善相关的不同HGG分子亚组，我们进行了全面的基因组分析。
我们根据720例胶质瘤的基因组、组织学和临床特征进行分析和比较（136例来自耶鲁大学，584例来自癌症基因组图谱）。
我们鉴定出一个HGG亚组（共6例，4例成人和2例儿童），其体细胞突变数量在统计学上显著增加（平均 = 9257.3对76.2，P = 0.002）。所有这些“超突变”肿瘤在聚合酶ε基因（POLE）的核酸外切酶结构域中都存在体细胞突变，表现出独特的遗传特征，其特点是基因组稳定性和C到A颠换增加。组织学上，它们都含有多核巨细胞或奇异细胞，有些伴有主要浸润的免疫细胞。1例成年患者和2例儿童患者在错配修复蛋白6（MSH6）基因中携带纯合种系突变。在成年人中，POLE突变在40岁以下的患者中观察到，并且与更长的无进展生存期相关。
我们鉴定出一个在基因组、组织学和临床上都不同的HGG亚组，其含有体细胞POLE突变且预后改善。识别独特的分子和病理HGG表型不仅对改进分类有意义，而且对潜在的靶向治疗也有意义。
