Comprehensive copy number profiles of breast cancer cell model genomes.
Comprehensive copy number profiles of breast cancer cell model genomes.
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DOI：
10.1186/bcr1370
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Lam WL
中科院分区：
文献类型：
--
作者：
Shadeo A;Lam WL
乳腺癌是全世界妇女中最常见的癌症，因此在组织病理学、免疫化学和家族史方面进行了广泛的研究。全基因组方法的进步促进了基因组变化及其对基因表达的后续影响的分子分类。细胞系提供了一种可再生资源，很容易用作乳腺癌细胞生物学的模型系统。对其基因组进行彻底的表征，以确定片段DNA丢失（潜在的含肿瘤抑制因子的位点）和获得（潜在的致癌位点）的区域，将极大地促进对来自此类细胞的生物学数据的解释。在这项研究中，我们使用新开发的全基因组平铺路径基因组DNA阵列，以前所未有的分辨率表征了七种最常用的乳腺癌模型细胞系的基因组。采用亚百万级分辨率平片阵列（SMRT）阵列比较基因组杂交（CGH）平台研究乳腺癌模型细胞系MCF-7、BT-474、MDA-MB-231、T47D、SK-BR-3、UACC-893和ZR-75-30的基因组变化。SMRT阵列CGH提供人类基因组的平片覆盖，允许断点检测，分辨率约为80千碱基。用荧光原位杂交验证了阵列CGH鉴定的两个新的离散变异。全基因组平铺路径阵列CGH分析发现了新的高水平改变，并对先前报道的产生候选基因的区域进行了精细定位。总之，观察到75个高水平收益和48个高水平损失，并记录了各自的边界。在染色体臂1p、8q、9p、11q、15q、17q和20q上观察到涉及多个水平变化的复杂改变。此外，对全基因组图谱的比对使得能够同时评估同一生物途径的多个组分的拷贝数状态。对含有表皮生长因子家族（表皮生长因子受体，HER2， HER3和HER4）相关基因的约60个位点的研究显示，所有7种细胞系在这些途径中都存在多个基因的拷贝数变化。作为实验模型，这些细胞系之间内在的遗传差异将影响它们的生物学和药理学反应。从我们的研究中推断出的这些基因组片段变化的知识将有助于解释来自这些细胞的生物学数据。
Breast cancer is the most commonly diagnosed cancer in women worldwide and consequently has been extensively investigated in terms of histopathology, immunochemistry and familial history. Advances in genome-wide approaches have contributed to molecular classification with respect to genomic changes and their subsequent effects on gene expression. Cell lines have provided a renewable resource that is readily used as model systems for breast cancer cell biology. A thorough characterization of their genomes to identify regions of segmental DNA loss (potential tumor-suppressor-containing loci) and gain (potential oncogenic loci) would greatly facilitate the interpretation of biological data derived from such cells. In this study we characterized the genomes of seven of the most commonly used breast cancer model cell lines at unprecedented resolution using a newly developed whole-genome tiling path genomic DNA array. Breast cancer model cell lines MCF-7, BT-474, MDA-MB-231, T47D, SK-BR-3, UACC-893 and ZR-75-30 were investigated for genomic alterations with the submegabase-resolution tiling array (SMRT) array comparative genomic hybridization (CGH) platform. SMRT array CGH provides tiling coverage of the human genome permitting break-point detection at about 80 kilobases resolution. Two novel discrete alterations identified by array CGH were verified by fluorescence in situ hybridization. Whole-genome tiling path array CGH analysis identified novel high-level alterations and fine-mapped previously reported regions yielding candidate genes. In brief, 75 high-level gains and 48 losses were observed and their respective boundaries were documented. Complex alterations involving multiple levels of change were observed on chromosome arms 1p, 8q, 9p, 11q, 15q, 17q and 20q. Furthermore, alignment of whole-genome profiles enabled simultaneous assessment of copy number status of multiple components of the same biological pathway. Investigation of about 60 loci containing genes associated with the epidermal growth factor family (epidermal growth factor receptor, HER2, HER3 and HER4) revealed that all seven cell lines harbor copy number changes to multiple genes in these pathways. The intrinsic genetic differences between these cell lines will influence their biologic and pharmacologic response as an experimental model. Knowledge of segmental changes in these genomes deduced from our study will facilitate the interpretation of biological data derived from such cells.
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