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第三和第八种最常见的儿童癌症。患有遗传性视网膜母细胞瘤（RB1基因的种系突变）的儿童在以后的生活中易患骨肉瘤。尽管最近在视网膜母细胞瘤和骨肉瘤的临床结果方面取得了进展，但去核仍然是视网膜母细胞瘤的常用治疗方法，骨肉瘤的存活率仅为50%以上，这强调了确定疾病进展的分子机制和开发更有效药物的必要性。我们实验室之前的发现表明，在没有Rb家族的情况下，aE2Fs调节表观遗传机制的募集，这是肿瘤形成所必需的，而在没有Rb家族的情况下，表观遗传基因的失调足以导致视网膜母细胞瘤的形成。然而，虽然RB1的功能丧失足以形成视网膜母细胞瘤，但骨肉瘤需要另一种肿瘤抑制因子TP53失活。通过对视网膜母细胞瘤和骨肉瘤的表观遗传景观的研究，在本研究计划中，我们希望确定为什么某些细胞类型比其他细胞类型更容易形成肿瘤，特别是在RB1失活后。我们的目标是在视网膜母细胞瘤中确定由激活因子E2Fs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形成中的作用以及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抗癌治疗的潜在新治疗靶点。

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.