Structure and function of genome plasticity in human cancer

人类癌症基因组可塑性的结构和功能

• 批准号: 10297843
• 负责人: Alex Kentsis
• 金额: $ 50.95万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-13 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297843
• 关键词: Adult; Alleles; Architecture; Biological; Cancer Biology; Carcinogenesis Mechanism; Cells; Chemoresistance; Child; Childhood; Childhood Solid Neoplasm; Chromatin; Chromatin Remodeling Factor; Clinical; Code; Complex; DNA; DNA Repair; DNA Sequence Rearrangement; Development; Elements; Engineering; Epigenetic Process; Functional disorder; Gene Expression; Gene Rearrangement; Genes; Genetic; Genetically Engineered Mouse; Genome; Genomic Instability; Genomic approach; Goals; Homologous Gene; Human; Human Engineering; Knowledge; Link; Malignant - descriptor; Malignant Neoplasms; Mission; Molecular; Molecular Target; Mouse Strains; Mus; Mutation; Nature; Normal Cell; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Signal Sequences; Public Health; Recurrence; Refractory; Research; Research Project Grants; Resistance; Rhabdoid Tumor; SMARCB1 gene; Signal Transduction; Site; Solid; Solid Neoplasm; Structure; Testing; Therapeutic; Transposase; Tumor Suppressor Genes; Tumor-Suppressor Gene Inactivation; United States National Institutes of Health; base; cancer subtypes; cell transformation; chemotherapy; chromatin remodeling; functional genomics; human disease; improved; in vivo; in vivo Model; inhibitor; innovation; insight; metaplastic cell transformation; molecular targeted therapies; novel; physiologic model; programs; stem cells; treatment strategy; tumor; tumorigenesis

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.

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。

项目成果

Why do young people get cancer?

• DOI: 10.1002/pbc.28335
• 发表时间: 2020-07
• 期刊: Pediatric blood & cancer
• 影响因子: 3.2
• 作者: Kentsis A

Germline SDHA mutations in children and adults with cancer.

• DOI: 10.1101/mcs.a002584
• 发表时间: 2018-08
• 期刊: Cold Spring Harbor molecular case studies
• 影响因子: 1.8
• 作者: Dubard Gault M;Mandelker D;DeLair D;Stewart CR;Kemel Y;Sheehan MR;Siegel B;Kennedy J;Marcell V;Arnold A;Al-Ahmadie H;Modak S;Robson M;Shukla N;Roberts S;Vijai J;Topka S;Kentsis A;Cadoo K;Carlo M;Latham Schwark A;Reznik E;Dinatale R;Hechtman J;Borras Flores E;Jairam S;Yang C;Li Y;Bayraktar EC;Ceyhan-Birsoy O;Zhang L;Kohlman W;Schiffman J;Stadler Z;Birsoy K;Kung A;Offit K;Walsh MF
• 通讯作者: Walsh MF

Intracardiac Low-grade Sarcoma Following Treatment for Ewing Sarcoma.

尤文肉瘤治疗后的心内低度肉瘤。

• DOI: 10.1097/mph.0000000000000754
• 发表时间: 2017
• 期刊: Journal of pediatric hematology/oncology
• 作者: Ortiz,MichaelV;Magnan,Heather;Slotkin,EmilyK;Ambati,SrikanthR;Chou,AlexanderJ;Wexler,LeonardH;Meyers,PaulA;Walsh,MichaelF;Heaton,Todd;Girardi,LeonardN;Wolden,SuzanneL;Price,AnitaP;Kennedy,JenniferA;Zehir,Ahmet;Hameed
• 通讯作者: Hameed

Analytical Validation of Clinical Whole-Genome and Transcriptome Sequencing of Patient-Derived Tumors for Reporting Targetable Variants in Cancer.

• DOI: 10.1016/j.jmoldx.2018.06.007
• 发表时间: 2018-11
• 期刊: The Journal of molecular diagnostics : JMD
• 作者: Wrzeszczynski KO;Felice V;Abhyankar A;Kozon L;Geiger H;Manaa D;London F;Robinson D;Fang X;Lin D;Lamendola-Essel MF;Khaira D;Dikoglu E;Emde AK;Robine N;Shah M;Arora K;Basturk O;Bhanot U;Kentsis A;Mansukhani MM;Bhagat G;Jobanputra V
• 通讯作者: Jobanputra V

The piggyBac-derived protein 5 (PGBD5) transposes both the closely and the distantly related piggyBac-like elements Tcr-pble and Ifp2.

• DOI: 10.1016/j.jmb.2021.166839
• 发表时间: 2021-04-02
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Helou L;Beauclair L;Dardente H;Piégu B;Tsakou-Ngouafo L;Lecomte T;Kentsis A;Pontarotti P;Bigot Y
• 通讯作者: Bigot Y