Cross-species genomic and epigenomic landscape of retinoblastoma.
Cross-species genomic and epigenomic landscape of retinoblastoma.
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DOI：
10.18632/oncotarget.1051
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Dyer MA
中科院分区：
文献类型：
--
作者：
Benavente CA;McEvoy JD;Finkelstein D;Wei L;Kang G;Wang YD;Neale G;Ragsdale S;Valentine V;Bahrami A;Temirov J;Pounds S;Zhang J;Dyer MA
人类癌症的基因工程小鼠模型（GEMMs）对于促进我们对肿瘤发生和进展的理解以及测试新的治疗方法非常重要。视网膜母细胞瘤是一种儿童期视网膜肿瘤，起源于RB1基因双等位基因失活。GEMMs忠实地概括了人类视网膜母细胞瘤的组织病理学、分子、细胞、形态计量学、神经解剖学和神经化学特征。在这项研究中，我们分析了小鼠视网膜母细胞瘤的基因组和表观基因组景观，并将它们与人类视网膜母细胞瘤进行了比较，以深入了解跨物种肿瘤进展的共同机制。与人类视网膜母细胞瘤相似，小鼠肿瘤的单核苷酸变异率很低。然而，小鼠视网膜母细胞瘤具有较高的非整倍性和区域和局灶性拷贝数变化率，这些变化取决于在发育中的小鼠视网膜中引发肿瘤发生的遗传病变。此外，小鼠视网膜母细胞瘤的表观遗传景观与人类肿瘤有显著不同，一些可用于人类视网膜母细胞瘤分子靶向治疗的途径，如SYK或MCL1，在GEMMs中并未被解除调控。综上所述，这些数据表明，小鼠和人类视网膜母细胞瘤在肿瘤进展机制方面存在重要差异，这些差异可能对转化研究测试这种破坏性儿童癌症的新疗法的疗效具有重要意义。
Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our understanding of tumor initiation and progression as well as for testing novel therapeutics. Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. GEMMs faithfully recapitulate the histopathology, molecular, cellular, morphometric, neuroanatomical and neurochemical features of human retinoblastoma. In this study, we analyzed the genomic and epigenomic landscape of murine retinoblastoma and compared them to human retinoblastomas to gain insight into shared mechanisms of tumor progression across species. Similar to human retinoblastoma, mouse tumors have low rates of single nucleotide variations. However, mouse retinoblastomas have higher rates of aneuploidy and regional and focal copy number changes that vary depending on the genetic lesions that initiate tumorigenesis in the developing murine retina. Furthermore, the epigenetic landscape in mouse retinoblastoma was significantly different from human tumors and some pathways that are candidates for molecular targeted therapy for human retinoblastoma such as SYK or MCL1 are not deregulated in GEMMs. Taken together, these data suggest there are important differences between mouse and human retinoblastomas with respect to the mechanism of tumor progression and those differences can have significant implications for translational research to test the efficacy of novel therapies for this devastating childhood cancer.
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影响因子：
11.2
作者：
Brennan RC;Federico S;Bradley C;Zhang J;Flores-Otero J;Wilson M;Stewart C;Zhu F;Guy K;Dyer MA
通讯作者：
Dyer MA
影响因子：
--
作者：
Amato A;Lentini L;Schillaci T;Iovino F;Di Leonardo A
通讯作者：
Di Leonardo A
影响因子：
4
作者：
Kenney, Renee Deehan;Heald, Rebecca
通讯作者：
Heald, Rebecca
影响因子：
64.8
作者：
Laurie, Nikia A.;Donovan, Stacy L.;Dyer, Michael A.
通讯作者：
Dyer, Michael A.
影响因子：
8
作者：
Fukasawa, K;Wiener, F;Mai, SB
通讯作者：
Mai, SB