Genetics of pediatric rhabdoid tumors

描述（由申请人提供）：横纹肌样瘤是一种临床侵袭性恶性肿瘤，通常出现在生命的前四年。中枢神经系统横纹肌样肿瘤（非典型畸胎瘤/横纹肌样肿瘤；AT/RT）、肾脏和软组织的横纹肌样肿瘤与22q11.2染色体上INI1/hSNF5肿瘤抑制基因的改变有关。AT/RT是唯一一种原发性遗传病因已被阐明的儿童脑肿瘤，多达35%的儿童可能易患INI1的种系缺失或突变。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是NIH脑肿瘤进展审查小组的目标，但对各种儿童和成人疾病具有更广泛的意义，这些疾病可能是由于参与染色质重塑的基因突变引起的。该计划的一个持续目标是确定INI1基因异质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有关，以及预后。在目标2中，我们将定义患者及其家庭中新生和遗传性种系缺失和突变的谱。初步数据表明，生殖系突变的亲本起源存在偏差，这将在更大的患者队列中进行探索。利用高密度单核苷酸多态性阵列的全基因组方法，将在目标3中用于询问包含INI1的染色体带22q11.2区域，以及鉴定可能与横纹肌样肿瘤发展相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特征将在aim 4中通过结合突变和表达分析进行探讨。公共卫生相关性：脑、肾和软组织横纹肌样瘤是临床侵袭性恶性肿瘤，主要影响4岁以下儿童。22号染色体上的INI1基因是大多数肿瘤中失活的关键抑癌基因。了解INI1失活的机制对于治疗分层以及最终为患者设计基于生物学的治疗策略非常重要。

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.