The Mechanism of Tumor Formation in Beckwith-Wiedemann Syndrome

 描述(由申请人提供)：本提案描述了一个五年计划，旨在发展表观遗传学、基于老鼠和人类细胞的疾病建模和癌症生物学方面的学术生涯。这期培训将补充我在分子遗传学和临床遗传学方面的培训。Marisa Bartolomei博士，表观遗传学和老鼠模型方面的著名专家，以及Garrett Brodeur博士，国际癌症生物学权威，将指导我的科学和职业发展。为了促进我的科学发展，我组建了一个咨询委员会，成员包括一位杰出的人类遗传学家和两位杰出的癌症生物学家。我的研究重点是Beckwith-Wiedemann综合征(BWS)的肿瘤形成。BWS是一种过度生长和肿瘤易感性疾病，每13,700名儿童中至少有1人受到影响。这些孩子中的许多人患上了癌症，最常见的是肝母细胞瘤和肾母细胞瘤。BWS是一系列临床疾病的一部分，从广泛性过度生长的经典特征到单个肢体或器官轻微的孤立过度生长。我以前的工作表明，即使具有细微的BWS特征的患者也会患上肿瘤。BWS是由11号染色体上的遗传和/或表观遗传变化引起的。在包括乳腺癌和结肠癌在内的许多癌症中也会发生类似的变化。研究BWS提供了一个独特的机会来研究一种罕见的疾病，以提供对常见肿瘤形成途径的洞察。在这项建议中，我们将使用我们的BWS患者队列超过250名患者来识别预测肿瘤风险增加的细微临床特征。利用从这些患者收集的成纤维细胞样本，我们正在开发第一个使用诱导多能干细胞(IPSCs)的基于人类细胞的BWS模型。IPSCs将被分化为肿瘤生长的细胞系(例如肝细胞)，并将进行全球分子图谱以确定参与肿瘤发生的途径。最后，我们设计了一个新的小鼠模型，专门研究11号染色体上的两个基因(H19和miR675)在生长和肿瘤形成中的独立作用。拟议研究的完成将改善BWS患者的肿瘤风险评估，并确定导致这些患者肿瘤形成的途径。这项工作是通过确定新的潜在肿瘤筛查方式和治疗目标，朝着改善患有BWS的儿童的护理迈出的必要的第一步。此外，该患者队列和这些模型将提供 对我的职业生涯来说，这是一种无价的资源。

 DESCRIPTION (provided by applicant): This proposal describes a 5-year plan for the development of an academic career in epigenetics, mouse and human cell-based modeling of disease, and cancer biology. This training period will complement my training in molecular and clinical genetics. Dr. Marisa Bartolomei, a renowned expert in epigenetics and mouse models, and Dr. Garrett Brodeur, an international authority in cancer biology, will mentor my scientific and career development. To facilitate my scientific development, I have assembled an advisory committee including an eminent human geneticist and two prominent cancer biologists. My research focuses on tumor formation in Beckwith-Wiedemann syndrome (BWS). BWS is an overgrowth and tumor predisposition disorder that affects at least 1 in 13,700 children. Many of these children develop cancer, most commonly hepatoblastomas and Wilms tumors. BWS is part of a spectrum of clinical disease ranging from classic features of generalized overgrowth to subtle isolated overgrowth of a single limb or organ. My previous work demonstrated that even patients with subtle BWS features develop tumors. BWS is caused by genetic and/or epigenetic changes on chromosome 11. Similar changes occur in a number of cancers including breast and colon cancer. Studying BWS presents a unique opportunity to study a rare disorder in order to provide insight into common tumor formation pathways. In this proposal, we will use our BWS patient cohort of over 250 patients to identify subtle clinical features predictive of increased tumor risk. Using fibroblast samples collected from these patients, we are developing the first human cell-based models of BWS using induced pluripotent stem cells (iPSCs). The iPSCs will be differentiated into the cell lineages in which tumors develop (e.g. hepatocytes) and global molecular profiling will be performed to identify pathways involved in tumorigenesis. Finally, we have designed a novel mouse model to specifically look at the independent role of two of the genes on chromosome 11 (H19 and miR675) in growth and tumor formation. The completion of the proposed studies will improve tumor risk assessment in BWS patients and define the pathways leading to tumor formation in these patients. This work is a necessary first step towards improving the care of children with BWS by identifying new potential tumor screening modalities and therapeutic targets. Additionally, this patient cohort and these models will provide an invaluable resource for my career endeavors.