Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Hepatology. 2010 Nov;52(5):1690-701. doi: 10.1002/hep.23847.
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.
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.
复发的癌症基因组异常是关键癌症基因存在的指标。尽管基因组技术的最新进展使人们对癌症基因组异常有了全面的了解，但从异常位点鉴定靶基因和生物标志物仍然很困难。为了促进人类肝细胞癌 (HCC) 中癌症基因的搜索，我们建立了一种使用高密度单核苷酸多态性阵列和无配对参考基因组分析癌症基因组拷贝数改变 (CNA) 的综合方案。我们通过重叠多个细胞系中具有功能验证和临床意义的共享异常位点来鉴定常见的 HCC 基因。在 23 个细胞系中发现了 653 个扩增子和 57 个纯合缺失 (HD)。为了寻找新的 HCC 基因，我们重叠异常位点以发现至少两个细胞系共享的 6 个 HD 和 126 个扩增子。我们选择了两个新基因，位于 3q26.3 重叠扩增子上的纤维连接蛋白 III 结构域包含 3B (FNDC3B) 和位于 11q13.2 重叠扩增子上的溶质载体家族 29 成员 2 (SLC29A2)，以研究它们在 HCC 肿瘤发生中的异常。FNDC3B 和 SLC29A2 的异常上调发生在多个 HCC 数据集中。在扩增细胞中敲低这些基因会降低细胞增殖、锚定非依赖性生长和异种移植模型中的肿瘤形成。重要的是，HCC 组织中 SLC29A2 的上调与晚期 (P = 0.0031)、血管侵犯 (P = 0.0353) 和患者生存不良 (P = 0.0325) 显著相关。未扩增 HCC 细胞中 FNDC3B 或 SLC29A2 的过表达通过激活信号转导和转录激活因子 3 信号通路促进细胞增殖。
使用来自用户生成或公共领域的数据并结合无配对参考基因组的标准化全基因组 CNA 分析方案已建立，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。
