Genome instability and epigenetic deregulation in retinoblastoma and osteosarcoma

描述(申请人提供)：视网膜母细胞瘤和骨肉瘤分别是儿童癌症的第三和八种最常见的形式。患有遗传性视网膜母细胞瘤的儿童-RB1基因的胚系突变-在他们晚年更容易患上骨肉瘤。尽管视网膜母细胞瘤和骨肉瘤的临床结果最近取得了进展，但眼球摘除仍然是视网膜母细胞瘤的常见治疗方法，骨肉瘤的存活率仅略高于50%，这突显了确定疾病进展的分子机制和开发更有效的药物的必要性。我们实验室以前的发现表明，aE2F调节在Rb家族缺失的情况下肿瘤形成所需的表观遗传机制的招募，并且在Rb缺失的情况下基因的表观遗传去调控足以导致视网膜母细胞瘤的形成。然而，虽然RB1的功能丧失足以导致视网膜母细胞瘤的形成，但骨肉瘤需要另一种肿瘤抑制因子TP53的失活。通过对视网膜母细胞瘤和骨肉瘤的表观遗传学图景的研究，在这项研究中，我们希望确定为什么某些类型的细胞比其他类型的细胞更容易形成肿瘤，特别是在RB1失活之后。我们的目标是确定视网膜母细胞瘤中受激活剂E2FS表观调控的Rb的直接转录靶点，并阐明表观遗传学和基因组不稳定性在骨肉瘤发生中的作用以及Rb如何参与这一过程。对肿瘤发生过程中染色质组织和基因表达变化的综合分析将有助于我们确定潜在的抗癌治疗新靶点。

DESCRIPTION (provided by applicant): Retinoblastoma and osteosarcoma are the third and eight most common forms of childhood cancers, respectively. Children with hereditary retinoblastoma -germline mutation in the RB1 gene- are predisposed to osteosarcoma later in their life. Despite recent progress in clinical outcomes in retinoblastoma and osteosarcoma, enucleation remains a frequent treatment for retinoblastoma and the survival rate for osteosarcoma is just over 50%, underscoring the need to identify molecular mechanisms responsible for disease progression and to develop more effective drugs. Previous finding from our laboratory suggest that aE2Fs regulate recruitment of the epigenetic machinery that is required for tumor formation in the absence of the Rb family and that epigenetic deregulation of genes in the absence of Rb is sufficient for retinoblastoma formation. However, while functional loss of RB1 is enough for retinoblastoma formation, osteosarcoma requires inactivation of an additional tumor suppressor, TP53. Through the study of the epigenetic landscape of retinoblastoma and osteosarcoma, in this research proposal we hope to determine why some cell types are more susceptible to tumor formation than other cell types, in particular following RB1 inactivation. We aim to identify direct transcriptional targets of Rb epigenetically regulated by activator E2Fs in retinoblastoma and elucidate the role of epigenetics and genome instability in osteosarcomagenesis and how Rb participates in this process. The use integrative analyses of the changes in chromatin organization and gene expression that occur during tumorigenesis will help us identify potential novel therapeutic targets for anticancer treatment.