A novel retinoblastoma therapy from genomic and epigenetic analyses.
A novel retinoblastoma therapy from genomic and epigenetic analyses.
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DOI：
10.1038/nature10733
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发表时间：
2012-01-11
期刊：
影响因子：
64.8
通讯作者：
Dyer, Michael A.
中科院分区：
文献类型：
--
作者：
Zhang, Jinghui;Benavente, Claudia A.;McEvoy, Justina;Flores-Otero, Jacqueline;Ding, Li;Chen, Xiang;Ulyanov, Anatoly;Wu, Gang;Wilson, Matthew;Wang, Jianmin;Brennan, Rachel;Rusch, Michael;Manning, Amity L.;Ma, Jing;Easton, John;Shurtleff, Sheila;Mullighan, Charles;Pounds, Stanley;Mukatira, Suraj;Gupta, Pankaj;Neale, Geoff;Zhao, David;Lu, Charles;Fulton, Robert S.;Fulton, Lucinda L.;Hong, Xin;Dooling, David J.;Ochoa, Kerri;Naeve, Clayton;Dyson, Nicholas J.;Mardis, Elaine R.;Bahrami, Armita;Ellison, David;Wilson, Richard K.;Downing, James R.;Dyer, Michael A.
视网膜母细胞瘤是一种侵袭性的儿童视网膜癌症，由RB1基因双等位基因缺失引发。为了确定与RB1缺失相关的突变，我们对视网膜母细胞瘤进行了全基因组测序。总体突变率很低；RB1是唯一已知发生突变的癌症基因。然后，我们评估了RB1在基因组稳定性中的作用，并考虑了癌症通路放松管制的非遗传机制。在这里，我们表明视网膜母细胞瘤基因组是稳定的，但多种癌症途径可以在表观遗传上解除调控。例如，原癌基因SYK在视网膜母细胞瘤中上调，是肿瘤细胞存活所必需的。用小分子抑制剂靶向SYK诱导视网膜母细胞瘤肿瘤细胞体外和体内死亡因此，RB1失活可能使肿瘤前细胞通过表观遗传机制获得多种癌症特征，直接或间接由RB1损失引起。这些数据为视网膜母细胞瘤的化疗干预提供了新的靶点。
Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of the RB1 gene. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated RB1’s role in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. Here we show that the retinoblastoma genome is stable, but multiple cancer pathways can be epigenetically deregulated. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, RB1 inactivation may allow preneoplastic cells to acquire multiple hallmarks of cancer through epigenetic mechanisms, resulting directly or indirectly from RB1 loss. These data provide novel targets for chemotherapeutic interventions of retinoblastoma.
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作者：
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通讯作者：
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通讯作者：
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