对 8000 个癌症基因组中染色体畸变的功能基因组分析。
Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes.
机构信息
Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.
出版信息
Genome Res. 2013 Feb;23(2):217-27. doi: 10.1101/gr.140301.112. Epub 2012 Nov 6.
A large database of copy number profiles from cancer genomes can facilitate the identification of recurrent chromosomal alterations that often contain key cancer-related genes. It can also be used to explore low-prevalence genomic events such as chromothripsis. In this study, we report an analysis of 8227 human cancer copy number profiles obtained from 107 array comparative genomic hybridization (CGH) studies. Our analysis reveals similarity of chromosomal arm-level alterations among developmentally related tumor types as well as a number of co-occurring pairs of arm-level alterations. Recurrent ("pan-lineage") focal alterations identified across diverse tumor types show an enrichment of known cancer-related genes and genes with relevant functions in cancer-associated phenotypes (e.g., kinase and cell cycle). Tumor type-specific ("lineage-restricted") alterations and their enriched functional categories were also identified. Furthermore, we developed an algorithm for detecting regions in which the copy number oscillates rapidly between fixed levels, indicative of chromothripsis. We observed these massive genomic rearrangements in 1%-2% of the samples with variable tumor type-specific incidence rates. Taken together, our comprehensive view of copy number alterations provides a framework for understanding the functional significance of various genomic alterations in cancer genomes.
一个大型的癌症基因组拷贝数谱数据库可以促进经常包含关键癌症相关基因的反复出现的染色体改变的识别。它还可用于探索染色体重排等低频率的基因组事件。在这项研究中,我们报告了对来自 107 项阵列比较基因组杂交(CGH)研究的 8227 个人类癌症拷贝数谱的分析。我们的分析揭示了发育相关肿瘤类型之间在染色体臂水平改变的相似性,以及许多同时发生的臂水平改变对。在不同肿瘤类型中鉴定出的反复出现的(“泛谱系”)局灶性改变显示出已知的癌症相关基因和与癌症相关表型(例如激酶和细胞周期)相关功能的基因富集。还鉴定了肿瘤类型特异性(“谱系受限”)改变及其富集的功能类别。此外,我们开发了一种用于检测拷贝数在固定水平之间快速波动的区域的算法,这表明发生了染色体重排。我们在 1%-2%的样本中观察到这些大规模的基因组重排,其肿瘤类型特异性发生率各不相同。总之,我们对拷贝数改变的全面观察为理解癌症基因组中各种基因组改变的功能意义提供了一个框架。