儿童中枢神经系统原始神经外胚层脑肿瘤生存和转移潜能的标志物：综合基因组分析。
Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis.
机构信息
Division of Hematology-Oncology, Arthur and Sonia Labatt Brain Tumour Research Centre, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
出版信息
Lancet Oncol. 2012 Aug;13(8):838-48. doi: 10.1016/S1470-2045(12)70257-7. Epub 2012 Jun 11.
BACKGROUND
Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease.
METHODS
We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers.
FINDINGS
We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037).
INTERPRETATION
LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials.
FUNDING
Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.
背景
儿童中枢神经系统原始神经外胚层脑肿瘤（PNETs）是非常侵袭性的脑肿瘤，其分子特征和最佳治疗方法尚不清楚。我们评估了一大组此类罕见肿瘤，以确定分子标志物，以加强对这种疾病的临床管理。
方法
我们从 9 个国家的 20 个机构获得了 142 例原发性大脑半球中枢神经系统 PNET 样本，并对其中 51 例样本进行了转录谱分析，对其中 77 例样本进行了拷贝数谱分析。我们使用聚类、基因和途径富集分析来识别肿瘤亚群和特定于群体的分子标志物，并应用免疫组织化学和基因表达分析来验证和评估亚群标志物的临床意义。
结果
我们确定了中枢神经系统 PNET 的三个分子亚群，它们通过原始神经（第 1 组）、寡神经（第 2 组）和间充质谱系（第 3 组）的基因表达特征来区分，具有谱系标志物 LIN28 和 OLIG2 的差异表达。第 1 组肿瘤患者中女性居多（男性：女性比例 0.61 为第 1 组，1.25 为第 2 组，1.63 为第 3 组；p=0.043[第 1 组与第 2 组和第 3 组]），最年轻（诊断时的中位年龄 2.9 岁[95%CI 2.4-5.2]为第 1 组，7.9 岁[6.0-9.7]为第 2 组，5.9 岁[4.9-7.8]为第 3 组；p=0.005），生存最差（中位生存 0.8 年[95%CI 0.5-1.2]为第 1 组，1.8 年[1.4-2.3]为第 2 组，4.3 年[0.8-7.8]为第 3 组；p=0.019）。第 3 组肿瘤患者在诊断时转移发生率最高（无远处转移：转移比 0.90 为第 3 组，2.80 为第 1 组，5.67 为第 2 组；p=0.037）。
解释
LIN28 和 OLIG2 是中枢神经系统 PNET 有前途的诊断和预后分子标志物，值得在前瞻性临床试验中进一步评估。
资金
加拿大卫生研究院、儿童脑研究所/ SickKids 基金会和 Samantha Dickson 脑肿瘤信托基金。
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