Beijing Key Lab of Traffic Data Analysis and Mining, School of Computer and Information Technology, Beijing Jiaotong University, No.3 Shangyuancun, Beijing, 100044, Haidian District, China.
Department of Medicine, Baylor College of Medicine, BCM451, Suite 100D, Houston, TX, 77030, USA.
BMC Med Genomics. 2019 Dec 12;12(1):192. doi: 10.1186/s12920-019-0620-6.
Neuroblastoma (NB) is the most common extracranial solid tumor found in children. The frequent gain/loss of many chromosome bands in tumor cells and absence of mutations found at diagnosis suggests that NB is a copy number-driven cancer. Despite the previous work, a systematic analysis that investigates the relationship between such frequent gain/loss of chromosome bands and patient prognosis has yet to be implemented.
First, we analyzed two NB CNV datasets to select chromosomal bands with a high frequency of gain or loss. Second, we applied a computational approach to infer sample-specific CNVs for each chromosomal band selected in step 1 based on gene expression data. Third, we applied univariate Cox proportional hazards models to examine the association between the resulting inferred copy number values (iCNVs) and patient survival. Finally, we applied multivariate Cox proportional hazards models to select chromosomal bands that remained significantly associated with prognosis after adjusting for critical clinical variables, including age, stage, gender, and MYCN amplification status.
Here, we used a computational method to infer the copy number variations (CNVs) of sample-specific chromosome bands from NB patient gene expression profiles. The resulting inferred CNVs (iCNVs) were highly correlated with the experimentally determined CNVs, demonstrating CNVs can be accurately inferred from gene expression profiles. Using this iCNV metric, we identified 58 frequent gain/loss chromosome bands that were significantly associated with patient survival. Furthermore, we found that 7 chromosome bands were still significantly associated with patient survival even when clinical factors, such as MYCN status, were considered. Particularly, we found that the chromosome band chr11p14 has high potential as a novel candidate cytogenetic biomarker for clinical use.
Our analysis resulted in a comprehensive list of prognostic chromosome bands supported by strong statistical evidence. In particular, the chr11p14 gain event provided additional prognostic value in addition to well-established clinical factors, including MYCN status, and thereby represents a novel candidate cytogenetic biomarker with high clinical potential. Additionally, this computational framework could be readily extended to other cancer types, such as leukemia.
神经母细胞瘤（NB）是儿童中最常见的颅外实体瘤。肿瘤细胞中许多染色体带的频繁增益/缺失和诊断时未发现突变表明 NB 是一种拷贝数驱动的癌症。尽管之前已经做了很多工作，但尚未进行系统分析，以调查这些染色体带的频繁增益/缺失与患者预后之间的关系。
首先，我们分析了两个 NB CNV 数据集，以选择增益或缺失频率较高的染色体带。其次，我们应用一种计算方法，根据基因表达数据推断步骤 1 中选择的每个染色体带的样本特异性 CNV。第三，我们应用单变量 Cox 比例风险模型来检验由此产生的推断拷贝数值（iCNV）与患者生存之间的关联。最后，我们应用多变量 Cox 比例风险模型，在调整关键临床变量（包括年龄、分期、性别和 MYCN 扩增状态）后，选择与预后显著相关的染色体带。
在这里，我们使用一种计算方法从 NB 患者基因表达谱中推断样本特异性染色体带的拷贝数变化（CNV）。由此产生的推断 CNV（iCNV）与实验确定的 CNV 高度相关，表明可以从基因表达谱中准确推断 CNV。使用此 iCNV 度量标准，我们确定了 58 个与患者生存显著相关的频繁增益/缺失染色体带。此外，我们发现，即使考虑到临床因素，如 MYCN 状态，7 个染色体带仍与患者生存显著相关。特别是，我们发现染色体带 chr11p14 具有作为临床应用的新型候选细胞遗传学生物标志物的高潜力。
我们的分析产生了一份由强有力的统计证据支持的全面预后染色体带清单。特别是，chr11p14 增益事件除了既定的临床因素（包括 MYCN 状态）外，还提供了额外的预后价值，因此代表了具有高临床潜力的新型候选细胞遗传学生物标志物。此外，这种计算框架可以很容易地扩展到其他癌症类型，如白血病。
