Overlapping High-Resolution Copy Number Alterations in Cancer Genomes Identified Putative Cancer Genes in Hepatocellular Carcinoma
Overlapping High-Resolution Copy Number Alterations in Cancer Genomes Identified Putative Cancer Genes in Hepatocellular Carcinoma
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DOI：
10.1002/hep.23847
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发表时间：
2010-11-01
期刊：
影响因子：
13.5
通讯作者：
Jou, Yuh-Shan
中科院分区：
文献类型：
--
作者：
Chen, Chian-Feng;Hsu, En-Chi;Jou, Yuh-Shan
复发性癌症基因组畸变是存在关键癌症基因的指标。尽管基因组技术的最新进展使人们对癌症基因组畸变有了一个全面的认识，但从畸变位点中鉴定靶基因和生物标志物仍然很困难。为了方便人类肝细胞癌（HCC）中癌症基因的搜索，我们建立了一个综合方案，利用高密度单核苷酸多态性阵列和未配对的参考基因组来分析癌症基因组中的拷贝数改变（CNAs）。我们通过在多个细胞系中重叠共享的异常位点，确定了常见的HCC基因，并进行了功能验证和临床意义。在23株细胞系中共发现653个扩增子和57个纯合缺失（hd）。为了寻找新的HCC基因，我们重叠了异常位点，发现了至少两个细胞系共有的6个hd和126个扩增子。我们选择了两个新基因，3q26.3重叠扩增子上含有3B的纤维连接蛋白III型结构域（FNDC3B）和11q13.2重叠扩增子上的溶质载体家族29成员2 (SLC29A2)，来研究它们在HCC肿瘤发生中的畸变。FNDC3B和SLC29A2的异常上调出现在多个HCC数据集中。在异种移植物模型中，在扩增细胞中敲低这些基因会降低细胞增殖、非锚定生长和肿瘤形成。重要的是，SLC29A2在HCC组织中的上调与晚期（P = 0.0031）、血管侵犯（P = 0.0353）和不良患者生存（P = 0.0325）显著相关。在未扩增的HCC细胞中，FNDC3B或SLC29A2过表达通过激活信号转导和转录3信号通路激活因子促进细胞增殖。结论：我们建立了一种标准化的全基因组CNA分析方案，使用来自用户生成或公共领域的数据与未配对的参考基因组进行标准化，以促进高通量检测癌症基因作为癌症诊断和治疗的重要靶基因和生物标志物。(肝脏病学52:1690 2010;1701)
Recurrent cancer genome aberrations are indicators of residing crucial cancer genes. Although recent advances in genomic technologies have led to a global view of cancer genome aberrations, the identification of target genes and biomarkers from the aberrant loci remains difficult. To facilitate searches of cancer genes in human hepatocellular carcinoma (HCC), we established a comprehensive protocol to analyze copy number alterations (CNAs) in cancer genomes using high-density single nucleotide polymorphism arrays with unpaired reference genomes. We identified common HCC genes by overlapping the shared aberrant loci in multiple cell lines with functional validation and clinical implications. A total of 653 amplicons and 57 homozygous deletions (HDs) were revealed in 23 cell lines. To search for novel HCC genes, we overlapped aberrant loci to uncover 6 HDs and 126 amplicons shared by at least two cell lines. We selected two novel genes, fibronectin type III domain containing 3B (FNDC3B) at the 3q26.3 overlapped amplicon and solute carrier family 29 member 2 (SLC29A2) at the 11q13.2 overlapped amplicon, to investigate their aberrations in HCC tumorigenesis. Aberrant up-regulation of FNDC3B and SLC29A2 occurred in multiple HCC data sets. Knockdown of these genes in amplified cells decreased cell proliferation, anchorage-independent growth, and tumor formation in xenograft models. Importantly, up-regulation of SLC29A2 in HCC tissues was significantly associated with advanced stages (P = 0.0031), vascular invasion (P = 0.0353), and poor patient survival (P = 0.0325). Overexpression of FNDC3B or SLC29A2 in unamplified HCC cells promoted cell proliferation through activation of the signal transducer and activator of transcription 3 signaling pathway. Conclusion: A standardized genome-wide CNA analysis protocol using data from user-generated or public domains normalized with unpaired reference genomes has been established to facilitate high-throughput detection of cancer genes as significant target genes and biomarkers for cancer diagnosis and therapy. (HEPATOLOGY 2010;52:1690-1701)