Genetics of pediatric rhabdoid tumors

小儿横纹肌样瘤的遗传学

• 批准号: 7827968
• 负责人: JACLYN A BIEGEL
• 金额: $ 26.69万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-13 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827968
• 关键词: 22q11.2; Address; Adult; Affect; Age-Years; Alleles; Anatomic Sites; Biological Assay; Brain; Brain Neoplasms; Candidate Disease Gene; Child; Childhood; Childhood Brain Neoplasm; Children' s Oncology Group; Choroid Plexus Carcinoma; Chromatin Remodeling Factor; Chromosomal Gain; Chromosome Band; Chromosomes; Chromosomes, Human, Pair 22; Cleft Palate; Clinical; Clinical Trials; Code; Collecting Ducts of Bellini Carcinoma; Congenital Heart Defects; Cytosine; DNA Sequence Rearrangement; Data; Deletion Mutation; Development; Developmental Delay Disorders; Disease; Epithelioid Sarcomas; Exons; Family; Frequencies; Functional RNA; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genomics; Genotype; Germ-Line Mutation; Goals; Guanine; Histologic; Immunohistochemistry; Individual; Inherited; Kidney; Lead; Life; Loss of Heterozygosity; Malignant Neoplasms; Maps; Mutation; Neuraxis; Nuclear; Outcome; Parents; Pathway interactions; Patients; Pattern; Phenotype; Progress Review Group; Proteins; RNA; Recruitment Activity; Reporting; Resolution; Rhabdoid Tumor; Risk; Role; SMARCB1 gene; Single Nucleotide Polymorphism; Somatic Mutation; Stratification; Therapeutic; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States National Institutes of Health; base; chromatin remodeling; clinical Diagnosis; cohort; deletion analysis; density; design; genome-wide; integrase interactor 1; medulloblastoma; member; novel; outcome forecast; prognostic; programs; promoter; protein expression; public health relevance; soft tissue; treatment response; tumor

DESCRIPTION (provided by applicant): Rhabdoid tumor is a clinically aggressive malignancy that generally presents in the first four years of life. Rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumor; AT/RT), kidney and soft tissues are associated with alterations of the INI1/hSNF5 tumor suppressor gene in chromosome 22q11.2. AT/RT is the only pediatric brain tumor for which the primary genetic etiology has been elucidated, and as many as 35% of children may have predisposing germline deletions or mutations of INI1. INI1 is a member of the SWI/SNF chromatin remodeling complex and functions to repress or activate gene transcription. Understanding the role of INI1 in tumor development specifically addresses the goals of the NIH Brain Tumor Progress Review Group, but has wider implications for a variety of pediatric and adult diseases that may arise as a consequence of mutations in genes involved in chromatin remodeling. A continuing goal of this program is to determine the spectrum of clinicopathologic manifestations of heterogeneous germline and somatic mutations of the INI1 gene. In aim 1, we will perform a comprehensive genomic analysis of the 22q11.2 region, including deletion analysis by FISH and MLPA, as well as direct sequencing. We will determine whether specific deletions or mutations are associated with anatomic site, as well as prognosis. In aim 2, we will define the spectrum of de novo and inherited germline deletions and mutations in patients and their families. Preliminary data suggests that there is a bias in the parent of origin of germline mutations, which will be explored in a larger patient cohort. A genome wide approach, using high density single nucleotide polymorphisms arrays, will be used in aim 3 to interrogate the region of chromosome band 22q11.2 which contains INI1, as well as to identify other chromosomal regions that may be related to rhabdoid tumor development. The characterization of potential candidate genes associated with clinical features and outcome will be explored in aim 4 using a combination of mutation and expression analyses. PUBLIC HEALTH RELEVANCE: Rhabdoid tumors of the brain, kidney and soft tissues are clinically aggressive malignancies that primarily affect children under four years of age. The INI1 gene on chromosome 22 is a key tumor suppressor inactivated in the majority of tumors. Understanding the mechanisms by which INI1 is inactivated will be important for treatment stratification, and ultimately designing biologically based therapeutic strategies for patients.

描述（由申请人提供）：色肽肿瘤是一种临床上侵略性的恶性肿瘤，通常在生命的头四年出现。中枢神经系统（非典型多霉素/色）肿瘤的横纹肌肿瘤，肾脏和软组织与INI1/HSNF5肿瘤抑制基因的改变有关22q11.2染色体中。 AT/RT是唯一阐明了主要遗传病因的小儿脑肿瘤，多达35％的儿童可能具有易于生殖线缺失或INI1的突变。 INI1是SWI/SNF染色质重塑复合物的成员，并且功能抑制或激活基因转录。了解INI1在肿瘤发育中的作用专门解决了NIH脑肿瘤进度审查组的目标，但对各种儿科和成人疾病具有更广泛的影响，这些疾病可能是由于与染色质重塑有关的基因突变而可能引起的。该计划的一个持续目标是确定INI1基因的异质种系和体细胞突变的临床病理表现范围。在AIM 1中，我们将对22q11.2区域进行全面的基因组分析，包括FISH和MLPA的缺失分析以及直接测序。我们将确定特定的缺失或突变是否与解剖部位以及预后有关。在AIM 2中，我们将定义从头开始的范围，并在患者及其家人中遗传了种系缺失和突变。初步数据表明，种系突变的起源父母存在偏见，这将在较大的患者队列中进行探讨。使用高密度单核苷酸多态性阵列的基因组范围的方法将用于AIM 3中，以询问包含INI1的染色体带22Q11.2的区域，并识别可能与色粒肿瘤发展有关的其他染色体区域。与临床特征和结果相关的潜在候选基因的表征将在AIM 4中使用突变和表达分析的组合进行探索。公共卫生相关性：大脑，肾脏和软组织的纹状体肿瘤是临床上侵略性的恶性肿瘤，主要影响四岁以下儿童。 22染色体上的INI1基因是在大多数肿瘤中灭活的关键肿瘤抑制剂。了解INI1被灭活的机制对于治疗分层至关重要，并最终为患者设计基于生物学的治疗策略。