Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach
Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach
复制标题
DOI：
10.1016/j.cell.2006.05.030
复制
发表时间：
2006-06-30
期刊：
影响因子：
64.5
通讯作者：
Lowe, Scott W.
中科院分区：
文献类型：
--
作者：
Zender, Lars;Spector, Mona S.;Lowe, Scott W.
人类肿瘤的异质性和不稳定性阻碍了仅通过基因组方法直接鉴定致癌突变。在此，我们描述了一种小鼠肝癌模型，起源于具有明确的癌症易感病变的祖细胞。对该小鼠模型和人类肝细胞癌肿瘤的全基因组分析显示，小鼠染色体9qA1（人类染色体11q22的合成区）反复扩增。基因表达分析表明cIAP1（一种已知的细胞凋亡抑制剂）和Yap（一种转录因子）是扩增子中的候选致癌基因。在其扩增的遗传背景下，cIAP1和Yap都加速了肿瘤的发生，并且是维持含有扩增子的肿瘤快速生长所必需的。此外，cIAP1和Yap共同促进肿瘤发生。我们的研究结果建立了一个易于处理的肝癌模型，确定了在同一基因组位点上通过共扩增而合作的两个癌基因，并为人类癌症基因的注释提供了一种有效的策略。
The heterogeneity and instability of human tumors hamper straightforward identification of cancer-causing mutations through genomic approaches alone. Herein we describe a mouse model of liver cancer initiated from progenitor cells harboring defined cancer-predisposing lesions. Genome-wide analyses of tumors in this mouse model and in human hepatocellular carcinomas revealed a recurrent amplification at mouse chromosome 9qA1, the syntenic region of human chromosome 11q22. Gene-expression analyses delineated cIAP1, a known inhibitor of apoptosis, and Yap, a transcription factor, as candidate oncogenes in the amplicon. In the genetic context of their amplification, both cIAP1 and Yap accelerated tumorigenesis and were required to sustain rapid growth of amplicon-containing tumors. Furthermore, cIAP1 and Yap cooperated to promote tumorigenesis. Our results establish a tractable model of liver cancer, identify two oncogenes that cooperate by virtue of their coamplification in the same genomic locus, and suggest an efficient strategy for the annotation of human cancer genes.