乳腺癌中稳定基因组区域的结构和基因特征：与化疗的相关性。
Structural and genic characterization of stable genomic regions in breast cancer: relevance to chemotherapy.
机构信息
Department of Pathology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
出版信息
Mol Oncol. 2012 Jun;6(3):347-59. doi: 10.1016/j.molonc.2012.01.001. Epub 2012 Jan 15.
BACKGROUND
Cancer genomes accumulate frequent and diverse chromosomal abnormalities as well as gene mutations but must maintain the ability to survive in vivo. We hypothesize that genetic selection acts to maintain tumour survival by preserving copy number of specific genes and genomic regions. Genomic regions and genes that remain unaltered in copy number and expression, respectively, may be essential for maintaining tumour survival.
METHODS
We analyzed copy number data of 243 previously reported breast tumours and computationally derived stable copy number regions. To identify genes in stable copy number regions with nominal changes in expression, datasets for tumour and normal samples were compared. Results were replicated by analysis of a series of independent copy number, expression and genomic sequencing studies. A subset of stable regions, including stable paralogous regions, were confirmed by quantitative PCR and fluorescence in situ hybridization (FISH) in 5 breast cancer cell lines. We deduced a comprehensive set of dually stable genes (i.e. maintaining nominal copy number and expression) which were categorized according to pathway and ontology assignments. The stability of genes encoding therapeutic drug targets was also assessed.
RESULTS AND CONCLUSION
Tumour genome analysis revealed 766 unstable (amplified and/or deleted) and 812 stable contiguous genomic regions. Replication analysis of an independent set of 171 breast tumours confirmed copy number stability of 1.3 Gb of the genome. We found that 5804 of these genes were dually stable. The composition of this gene set remained essentially unchanged (<2% reduction) after accounting for commonly mutated breast cancer genes found by sequencing and differential expression. The stable breast cancer genome is enriched for cellular metabolism, regulation of gene expression, DNA packaging (chromatin and nucleosome assembly), and regulation of apoptosis functions. Stable genes participating in multiple essential pathways were consistently found to be targets of chemotherapies. Preservation of stable, essential genes may be related to the effectiveness of certain chemotherapeutic agents that act on multiple gene products in this set.
背景
癌症基因组积累了频繁且多样的染色体异常和基因突变，但必须保持在体内存活的能力。我们假设遗传选择通过保留特定基因和基因组区域的拷贝数来维持肿瘤的存活。在拷贝数和表达方面分别保持不变的基因组区域和基因，可能对于维持肿瘤的存活至关重要。
方法
我们分析了 243 个先前报道的乳腺癌肿瘤的拷贝数数据，并通过计算推导了稳定的拷贝数区域。为了鉴定在表达上有标称变化的稳定拷贝数区域中的基因，我们比较了肿瘤和正常样本的数据集。通过对一系列独立的拷贝数、表达和基因组测序研究的分析，对结果进行了复制。通过在 5 个乳腺癌细胞系中进行定量 PCR 和荧光原位杂交（FISH）验证，证实了稳定区域的一个子集，包括稳定的同源区域。我们推断了一组全面的双重稳定基因（即维持标称拷贝数和表达），根据途径和本体论分配进行了分类。还评估了编码治疗药物靶点的基因的稳定性。
结果和结论
肿瘤基因组分析揭示了 766 个不稳定（扩增和/或缺失）和 812 个稳定的连续基因组区域。对一组独立的 171 个乳腺癌肿瘤的复制分析证实了基因组 1.3 Gb 的拷贝数稳定性。我们发现，其中 5804 个基因是双重稳定的。在考虑到测序和差异表达发现的常见乳腺癌基因突变后，这个基因集的组成基本上没有变化（<2%的减少）。这个稳定的乳腺癌基因组富含细胞代谢、基因表达调控、DNA 包装（染色质和核小体组装）以及凋亡功能的调控。参与多个必需途径的稳定基因被一致认为是多种化疗药物的靶点。稳定的必需基因的保存可能与作用于该基因集中多个基因产物的某些化疗药物的有效性有关。
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