Structure and function of genome plasticity in human cancer

项目摘要 尽管付出了巨大的努力，但儿童和成人实体瘤（如横纹肌样瘤）的长期治愈率仍然很低， 并不令人满意。对强化化疗的耐药性几乎是普遍的，并且分子靶点是 治疗方法在很大程度上是不确定的。例如，SMARCB 1的失活突变导致横纹肌样瘤，但 它们的分子病理生理学和遗传学仍然知之甚少。我们现在发现， 儿童和不同成人实体瘤，包括横纹肌样瘤，表达PGBD 5，一种DNA转座酶， 衍生的人类基因。我们现在已经发现，人类横纹肌样瘤和许多实体瘤的特点是， 通过先前未知的涉及PGBD 5特异性信号序列（PSS）的体细胞缺失和倒位， 他们的断点。值得注意的是，PGBD 5的DNA转座酶活性是必要的，也是足够的。 细胞转化，并诱导复发性和位点特异性基因组重排，导致合作 肿瘤抑制基因的失活。这项建议的中心假设是，定义遗传和 表观遗传机制PGBD 5诱导的肿瘤发生将确定PGBD 5诱导的肿瘤发生的根本原因。 特别是实体瘤和难治性横纹肌样瘤。申请人将通过以下方式检验这一假设： 研究PGBD5诱导的细胞转化和横纹肌样肿瘤发生的分子机制 使用原代人类和基因工程小鼠肿瘤。目的1将阐明遗传和表观遗传 PGBD 5诱导的细胞转化的机制，目的是确定PGBD 5靶点， 恶性转化所必需的，以及控制其诱导的分子机制。目标2将 寻求PGBD5诱导的基因组重排与SMARCB 1合作的初步证据 横纹肌样肿瘤中的突变，并使用发育忠实的小鼠确定PGBD 5的功能 横纹肌样肿瘤模型。该项目的成功完成预计将产生必要的分子 PGBD5诱导的肿瘤发生机制，从而提供了一个基本的生物学和 这对认识和治疗实体瘤具有广泛而持久的意义。

Project Summary Despite intense efforts, the long-term cure rates of childhood and adult solid tumors such as rhabdoid tumors are not satisfactory. Resistance to intensive chemotherapy is nearly universal, and targets for molecular therapies are largely undefined. For example, inactivating mutations of SMARCB1 cause rhabdoid tumors, but their molecular pathophysiology and genetics remain poorly understood. We have now found that the majority of childhood and distinct adult solid tumors, including rhabdoid tumors, express PGBD5, a DNA transposase- derived human gene. We have now found that human rhabdoid and numerous solid tumors are characterized by previously unknown somatic deletions and inversions involving PGBD5-specific signal sequences (PSS) at their breakpoints. Remarkably, PGBD5's DNA transposase enzymatic activity is both necessary and sufficient for cell transformation, and induces recurrent and site-specific genomic rearrangements, leading to cooperative inactivation of tumor suppressor genes. The central hypothesis of this proposal is that defining the genetic and epigenetic mechanisms PGBD5-induced tumorigenesis will identify fundamental causes of PGBD5-induced solid tumors and refractory rhabdoid tumors in particular. The applicant will test this hypothesis by investigating the molecular mechanisms of PGBD5-induced cell transformation and rhabdoid tumorigenesis using primary human and genetically-engineered mouse tumors. Aim 1 will elucidate genetic and epigenetic mechanisms of PGBD5-induced cell transformation, with the goal of identifying PGBD5 targets that are necessary for malignant transformation, and molecular mechanisms that control their induction. Aim 2 will pursue the preliminary evidence that PGBD5-induced genomic rearrangements cooperate with SMARCB1 mutations in rhabdoid tumors and determine the function of PGBD5 using developmentally faithful mouse rhabdoid tumor models in vivo. Successful completion of this project is expected to yield essential molecular mechanisms of PGBD5-induced tumorigenesis, thus providing key insights into a fundamental biological and clinical problem, which should have broad and lasting significance for understanding and treating solid tumors.