Pfister Stefan, Remke Marc, Benner Axel, Mendrzyk Frank, Toedt Grischa, Felsberg Jörg, Wittmann Andrea, Devens Frauke, Gerber Nicolas U, Joos Stefan, Kulozik Andreas, Reifenberger Guido, Rutkowski Stefan, Wiestler Otmar D, Radlwimmer Bernhard, Scheurlen Wolfram, Lichter Peter, Korshunov Andrey
Division of Molecular Genetics and Biostatistics and Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
J Clin Oncol. 2009 Apr 1;27(10):1627-36. doi: 10.1200/JCO.2008.17.9432. Epub 2009 Mar 2.
Medulloblastoma is the most common malignant brain tumor in children. Current treatment decisions are based on clinical variables. Novel tumor-derived biomarkers may improve the risk stratification of medulloblastoma patients.
A model for the molecular risk stratification was proposed from an array-based comparative genomic hybridization (array-CGH) screen (n = 80). Fluorescence in situ hybridization (FISH) analyses for chromosome arms 6q, 17p, and 17q and the MYC and MYCN loci were performed in an independent validation set (n = 260). Copy number aberrations were correlated with clinical, histologic, and survival data.
Gain of 6q and 17q and genomic amplification of MYC or MYCN were each associated with poor outcome in the array-CGH study (n = 80). In contrast, all patients with 6q-deleted tumors survived. Given these findings, the following hierarchical molecular staging system was defined: (1) MYC/MYCN amplification, (2) 6q gain, (3) 17q gain, (4) 6q and 17q balanced, and (5) 6q deletion. The prognostic value of this staging system was investigated by FISH analysis (n = 260). The addition of molecular markers to clinical risk factors resulted in the identification of a large proportion of patients (72 of 260 patients; 30%) at high risk for relapse and death who would be considered standard risk by application of clinical variables alone.
Genomic aberrations in medulloblastoma are powerful independent markers of disease progression and survival. By adding genomic markers to established clinical and histologic variables, outcome prediction can be substantially improved. Because the analyses can be conducted on routine paraffin-embedded material, it will be especially feasible to use this novel molecular staging system in large multicenter clinical trials.
髓母细胞瘤是儿童最常见的恶性脑肿瘤。目前的治疗决策基于临床变量。新型肿瘤衍生生物标志物可能会改善髓母细胞瘤患者的风险分层。
基于阵列比较基因组杂交（array-CGH）筛选（n = 80）提出了一种分子风险分层模型。在一个独立验证集（n = 260）中对6号染色体长臂、17号染色体短臂和17号染色体长臂以及MYC和MYCN基因座进行荧光原位杂交（FISH）分析。拷贝数畸变与临床、组织学和生存数据相关。
在array-CGH研究（n = 80）中，6号染色体长臂和17号染色体长臂的获得以及MYC或MYCN的基因组扩增均与不良预后相关。相比之下，所有6号染色体缺失肿瘤的患者均存活。基于这些发现，定义了以下分级分子分期系统：（1）MYC/MYCN扩增，（2）6号染色体长臂获得，（3）17号染色体长臂获得，（4）6号染色体长臂和17号染色体长臂平衡，以及（5）6号染色体缺失。通过FISH分析（n = 260）研究了该分期系统的预后价值。将分子标志物添加到临床风险因素中，发现很大一部分患者（260例患者中的72例；30%）复发和死亡风险高，而仅应用临床变量时这些患者会被视为标准风险。
髓母细胞瘤中的基因组畸变是疾病进展和生存的有力独立标志物。通过将基因组标志物添加到既定的临床和组织学变量中，可以显著改善预后预测。由于可以在常规石蜡包埋材料上进行分析，因此在大型多中心临床试验中使用这种新型分子分期系统将特别可行。
