An integrated analysis of molecular aberrations in NCI-60 cell lines.
An integrated analysis of molecular aberrations in NCI-60 cell lines.
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DOI：
10.1186/1471-2105-11-495
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发表时间：
2010-10-06
影响因子：
3
通讯作者：
Yeang CH
中科院分区：
文献类型：
--
作者：
Yeang CH
癌症是一种复杂的疾病，其中各种类型的分子畸变驱动恶性肿瘤的发展和进展。对多种类型的分子畸变进行大规模筛查（例如，突变、拷贝数变异、DNA甲基化、基因表达）在癌症的预后和研究中变得越来越重要。因此，一个计算模型集成多种类型的信息是必不可少的综合数据的分析。我们提出了一个综合的建模框架，以确定各种分子畸变和基因表达在癌症中的统计和推定的因果关系。为了减少大量探测特征之间的虚假关联，我们依次应用了三层逻辑回归模型，增加了关于连接分子畸变和基因表达的可能机制的复杂性和不确定性。第1层模型将基因表达与相同位点上的分子畸变相关联。第2层模型将表达与不同位点上的畸变相关联，但具有已知的机制联系。第3层模型将表情与具有未知机械联系的非局部畸变相关联。我们将分层模型应用于NCI-60癌细胞系的集成数据集，并通过大规模统计分析验证了结果。此外，我们发现/重申了以下突出的联系：（1）蛋白质表达通常与mRNA表达一致。（2）复合性局部畸变可调控多种基因的表达。例如，CDKN2A表达被移码突变或DNA甲基化抑制。（3）白血病中染色体6q的扩增使MYB的表达升高，MYB下游其它染色体上的靶点也相应上调。（4）染色体3p的扩增和PAX3的低甲基化共同提高了MITF在黑色素瘤中的表达，从而上调了MITF下游靶点。（5）TP53的突变与其直接靶基因呈负相关。对NCI-60数据的分析结果证明了分层模型对癌症基因组数据输入流的实用性。随后将对选定的突出链接进行实验验证，并将分层建模框架应用于其他综合数据集。
Cancer is a complex disease where various types of molecular aberrations drive the development and progression of malignancies. Large-scale screenings of multiple types of molecular aberrations (e.g., mutations, copy number variations, DNA methylations, gene expressions) become increasingly important in the prognosis and study of cancer. Consequently, a computational model integrating multiple types of information is essential for the analysis of the comprehensive data. We propose an integrated modeling framework to identify the statistical and putative causal relations of various molecular aberrations and gene expressions in cancer. To reduce spurious associations among the massive number of probed features, we sequentially applied three layers of logistic regression models with increasing complexity and uncertainty regarding the possible mechanisms connecting molecular aberrations and gene expressions. Layer 1 models associate gene expressions with the molecular aberrations on the same loci. Layer 2 models associate expressions with the aberrations on different loci but have known mechanistic links. Layer 3 models associate expressions with nonlocal aberrations which have unknown mechanistic links. We applied the layered models to the integrated datasets of NCI-60 cancer cell lines and validated the results with large-scale statistical analysis. Furthermore, we discovered/reaffirmed the following prominent links: (1)Protein expressions are generally consistent with mRNA expressions. (2)Several gene expressions are modulated by composite local aberrations. For instance, CDKN2A expressions are repressed by either frame-shift mutations or DNA methylations. (3)Amplification of chromosome 6q in leukemia elevates the expression of MYB, and the downstream targets of MYB on other chromosomes are up-regulated accordingly. (4)Amplification of chromosome 3p and hypo-methylation of PAX3 together elevate MITF expression in melanoma, which up-regulates the downstream targets of MITF. (5)Mutations of TP53 are negatively associated with its direct target genes. The analysis results on NCI-60 data justify the utility of the layered models for the incoming flow of cancer genomic data. Experimental validations on selected prominent links and application of the layered modeling framework to other integrated datasets will be carried out subsequently.
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影响因子：
4.3
作者：
Guan Y;Myers CL;Lu R;Lemischka IR;Bult CJ;Troyanskaya OG
通讯作者：
Troyanskaya OG
影响因子：
4.3
作者：
Hoek, Keith S.;Schlegel, Natalie C.;Steingrimsson, Eirikur
通讯作者：
Steingrimsson, Eirikur
影响因子：
5.7
作者：
Blower, Paul E.;Verducci, Joseph S.;Sadee, Wolfgang
通讯作者：
Sadee, Wolfgang
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
11.2
作者：
Amundson, Sally A.;Do, Khanh T.;Fornace, Albert J., Jr.
通讯作者：
Fornace, Albert J., Jr.