Asgharzadeh Shahab, Pique-Regi Roger, Sposto Richard, Wang Hong, Yang Yujun, Shimada Hiroyuki, Matthay Katherine, Buckley Jonathan, Ortega Antonio, Seeger Robert C
Department of Pediatrics, Division of Hematology-Oncology, Childrens Hospital Los Angeles and Saban Research Institute, University of Southern California, Los Angeles, CA, USA.
J Natl Cancer Inst. 2006 Sep 6;98(17):1193-203. doi: 10.1093/jnci/djj330.
The aggressiveness of metastatic neuroblastomas that lack MYCN gene amplification varies with age--they are least aggressive when diagnosed in patients younger than 12 months and most aggressive when diagnosed in patients older than 24 months. However, age at diagnosis is not always associated with patient survival. We examined whether molecular classification of metastatic neuroblastomas without MYCN gene amplification at diagnosis using gene expression profiling could improve the prediction of risk of disease progression.
We used Affymetrix microarrays to determine the gene expression profiles of 102 untreated primary neuroblastomas without MYCN gene amplification obtained from children whose ages at diagnosis ranged from 0.1 to 151 months. A supervised method using diagonal linear discriminant analysis was devised to build a multigene model for predicting risk of disease progression. The accuracy of the model was evaluated using nested cross-validations, permutation analyses, and gene expression data from 15 additional tumors obtained at disease progression.
An expression profile model using 55 genes defined a tumor signature that distinguished two groups of patients from among those older than 12 months at diagnosis and clinically classified as having high-risk disease, those with a progression-free survival (PFS) rate of 16% (95% confidence interval [CI] = 8% to 28%), and those with a PFS rate of 79% (95% CI = 57% to 91%) (P<.01). These tumor signatures also identified two groups of patients with PFS of 15% (95% CI = 7% to 27%) and 69% (95% CI = 40% to 86%) (P<.01) from among patients who were older than 18 months at diagnosis. The gene expression signature of untreated molecular high-risk tumors was also present in progressively growing tumors.
Gene expression signatures of tumors obtained at diagnosis from patients with clinically indistinguishable high-risk, metastatic neuroblastomas identify subgroups with different outcomes. Accurate identification of these subgroups with gene expression profiles may facilitate development, implementation, and analysis of clinical trials aimed at improving outcome.
缺乏MYCN基因扩增的转移性神经母细胞瘤的侵袭性随年龄而异——在12个月以下患者中诊断出时侵袭性最低，在24个月以上患者中诊断出时侵袭性最高。然而，诊断时的年龄并不总是与患者生存率相关。我们研究了使用基因表达谱对诊断时无MYCN基因扩增的转移性神经母细胞瘤进行分子分类是否能改善疾病进展风险的预测。
我们使用Affymetrix微阵列来确定从诊断年龄在0.1至151个月的儿童中获得的102例未经治疗的原发性神经母细胞瘤（无MYCN基因扩增）的基因表达谱。设计了一种使用对角线性判别分析的监督方法来构建用于预测疾病进展风险的多基因模型。使用嵌套交叉验证、置换分析以及疾病进展时获得的另外15个肿瘤的基因表达数据来评估模型的准确性。
使用55个基因的表达谱模型定义了一种肿瘤特征，该特征在诊断时年龄大于12个月且临床分类为高危疾病的患者中区分出两组，一组无进展生存期（PFS）率为16%（95%置信区间[CI]=8%至28%），另一组PFS率为79%（95%CI=57%至91%）（P<0.01）。这些肿瘤特征还在诊断时年龄大于18个月的患者中识别出两组PFS分别为15%（95%CI=7%至27%）和69%（95%CI=40%至86%）的患者（P<0.01）。未经治疗的分子高危肿瘤的基因表达特征在进展性生长的肿瘤中也存在。
从临床上难以区分的高危转移性神经母细胞瘤患者诊断时获得的肿瘤基因表达特征可识别出具有不同预后的亚组。通过基因表达谱准确识别这些亚组可能有助于旨在改善预后的临床试验的开展、实施和分析。
