The Mechanism of Tumor Formation in Beckwith-Wiedemann Syndrome

 描述（由申请人提供）：该提案描述了一个5年计划，用于发展表观遗传学，基于小鼠和人类细胞的疾病建模和癌症生物学的学术生涯。这段培训期将补充我在分子和临床遗传学方面的培训。著名的表观遗传学和小鼠模型专家玛丽莎·巴托洛梅博士和癌症生物学国际权威加勒特·布罗德博士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，其中包括一位著名的人类遗传学家和两位著名的癌症生物学家。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，影响至少1/13，700的儿童。这些儿童中的许多人患上癌症，最常见的是肝母细胞瘤和肾母细胞瘤。BWS是临床疾病谱的一部分，范围从全身性过度生长的经典特征到单个肢体或器官的细微孤立过度生长。我以前的工作表明，即使是具有轻微BWS特征的患者也会发生肿瘤。BWS由11号染色体上的遗传和/或表观遗传变化引起。类似的变化发生在许多癌症中，包括乳腺癌和结肠癌。研究BWS提供了一个独特的机会来研究一种罕见的疾病，以便深入了解常见的肿瘤形成途径。在本提案中，我们将使用超过250名患者的BWS患者队列来识别预测肿瘤风险增加的微妙临床特征。使用从这些患者中收集的成纤维细胞样本，我们正在使用诱导多能干细胞（iPSC）开发第一个基于人类细胞的BWS模型。iPSC将分化成肿瘤发展的细胞谱系（例如肝细胞），并将进行整体分子谱分析以鉴定参与肿瘤发生的途径。最后，我们设计了一种新的小鼠模型，专门研究11号染色体上的两个基因（H19和miR 675）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靶点来改善BWS儿童护理的必要的第一步。此外，该患者队列和这些模型将提供 对我的事业来说是无价的资源

 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.