Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Genes Chromosomes Cancer. 2012 Jan;51(1):77-82. doi: 10.1002/gcc.20934. Epub 2011 Oct 27.
DNA copy number aberrations (CNA) and subsequent altered gene expression profiles (mRNA levels) are characteristic features of cancerous cells. Integrative genomic analysis aims to identify recurrent CNA that may have a potential role in cancer development, assuming that gene amplification is accompanied by overexpression, while deletions give rise to downregulation of gene expression. We propose a segmented regression-based approach to identify CNA-driven alteration of gene expression profiles. Segmented regression allows to fit piecewise linear models in different domains of CNA joined by a change-point, where the mRNA-CNA relationship undergoes structural changes. Here, we illustrate the implementation and applicability of the proposed model using 1,161 chromosome fragments detected as DNA CNA in primary tumors from 97 breast cancer patients. We identified significant CNA-driven changes in gene expression levels for 341 chromosome fragments, of which 72 showed a nonlinear relationship to CNA. For 59 of 72 chromosome fragments (82%), we observed an initial increase in mRNA levels due to changes in CNA. After the change-point was passed, the mRNA levels reached a plateau, and a further increase in DNA copy numbers did not induce further elevation in mRNA levels. In contrast, for 13 chromosome fragments, the change-point marked the point where mRNA production accelerated. We conclude that segmented regression modeling may provide valuable insights into the impact CNA have on gene expression in cancer cells.
DNA 拷贝数异常（CNA）和随后改变的基因表达谱（mRNA 水平）是癌细胞的特征。综合基因组分析旨在识别可能在癌症发展中起作用的反复出现的 CNA，假设基因扩增伴随着过表达，而缺失则导致基因表达下调。我们提出了一种基于分段回归的方法来识别 CNA 驱动的基因表达谱改变。分段回归允许在 CNA 的不同域中拟合分段线性模型，这些域由一个变化点连接，其中 mRNA-CNA 关系发生结构变化。在这里，我们使用 97 名乳腺癌患者的原发性肿瘤中检测到的 1161 个染色体片段来举例说明所提出模型的实现和适用性。我们确定了 341 个染色体片段的基因表达水平的显著 CNA 驱动变化，其中 72 个显示出与 CNA 的非线性关系。对于 72 个染色体片段中的 59 个（82%），我们观察到由于 CNA 的变化导致 mRNA 水平最初增加。超过变化点后，mRNA 水平达到一个平台，进一步增加 DNA 拷贝数不会引起 mRNA 水平的进一步升高。相比之下，对于 13 个染色体片段，变化点标志着 mRNA 产生加速的点。我们得出结论，分段回归模型可能为 CNA 对癌细胞中基因表达的影响提供有价值的见解。
