Genetics of pediatric rhabdoid tumors

描述(申请人提供)：横纹肌样瘤是一种临床上侵袭性的恶性肿瘤，通常出现在生命的头四年。中枢神经系统横纹肌样肿瘤(非典型畸胎样/横纹肌样肿瘤；AT/RT)、肾脏和软组织与染色体22q11.2的INI1/hSNF5肿瘤抑制基因改变相关。AT/RT是唯一一种主要遗传病因已被阐明的儿童脑肿瘤，多达35%的儿童可能具有诱发性的INI1胚系缺失或突变。INI1是SWI/SNF染色质重塑复合体的成员，具有抑制或激活基因转录的功能。了解INI1在肿瘤发展中的作用具体涉及NIH脑肿瘤进展审查小组的目标，但对可能因染色质重塑相关基因突变而出现的各种儿科和成人疾病具有更广泛的影响。该计划的一个持续目标是确定INI1基因的异种种系和体细胞突变的临床病理表现谱。在目标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相关。在目标2中，我们将定义患者及其家庭中从头开始和遗传的生殖系缺失和突变的谱。初步数据表明，生殖系突变的父母存在偏见，这将在更大的患者队列中进行探索。在AIM 3中，将使用高密度单核苷酸多态阵列的全基因组方法来询问包含INI1的染色体带22q11.2区域，以及识别可能与横纹肌样肿瘤发生相关的其他染色体区域。在目标4中，将结合突变和表达分析来探索与临床特征和结果相关的潜在候选基因的特征。公共卫生相关性：大脑、肾脏和软组织的横纹肌样肿瘤是临床上侵袭性的恶性肿瘤，主要影响四岁以下的儿童。位于22号染色体上的INI1基因是一种关键的肿瘤抑制基因，在大多数肿瘤中处于失活状态。了解INI1失活的机制对于治疗分层和最终为患者设计基于生物的治疗策略将是重要的。

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.