Genetics of Pediatric Rhabdoid Tumors

描述：(改编自研究人员的摘要)横纹肌样瘤是一种 一种迅速致命的恶性肿瘤，通常出现在 生活。最常见的表现部位是大脑和肾脏。我们和 其他人使用细胞遗传学和分子研究相结合的方法来定义 22q11.2的临界区含有横纹肌样肿瘤抑制基因。 最近，Versteege等人(1998)报道了hSNF5/INI1作为候选基因 肾和肾外横纹肌样肿瘤。我们鉴定了生殖系和体细胞 儿童中枢神经系统横纹肌样瘤INI1基因突变的研究 (Biegel等人，1999)，现在已经记录了患者的生殖系突变 脑部和肾脏的原发肿瘤。INI1是SWIJSNF的成员 复合体，几种细胞周期和依赖于ATP的核小体重塑之一 哺乳动物细胞中的复合体。SWTJSNF复合体在两种激活中的作用 以及对下游靶基因的抑制。在本提案中，我们将定义 儿童横纹肌样瘤中INI1缺失和突变的谱 大脑、肾脏和软组织。遗传生殖系和新生生殖系的频率 患者及其父母的突变将被确定。纯合缺失 在11%的肿瘤中观察到染色体带22q 11.2上的INI1基因突变， 而在近50个人中发现了无稽之谈和移码突变 案件的百分比。相比之下，大约25%的原发肿瘤 证明INI1的外显子-内含子1区域的变化导致 无INI1基因表达。我们认为在这一过程中基因组重排 CpG二核苷酸区域或高甲基化可降低INI1的表达。 因此，其他22号染色体的单体或缺失将导致纯合子 INI1失活，导致肿瘤形成。Intl的独特性 横纹肌样肿瘤的突变也将在这个计划中解决， 特别强调评估更大系列的髓母细胞瘤-原始 脑部的神经外胚层肿瘤和脉络丛癌，以及 儿童横纹肌肉瘤系列。这些研究将导致更好的 了解Int1在恶性肿瘤发生发展中的作用 在确定患者和患者的诊断和预后方面的改进 家庭，最终是基于生物的治疗策略。

DESCRIPTION: (Adapted from the investigator's abstract) Rhabdoid tumor is a rapidly fatal malignancy that generally presents in the first two years of life. The most common sites of presentation are the brain and kidney. We and others used a combination of cytogenetic and molecular studies to define a critical region in 22q11.2 that contained a rhabdoid tumor suppressor gene. Recently, Versteege et al (1998) reported hSNF5/INI1 as a candidate gene for renal and extrarenal rhabdoid tumors. We identified germline and somatic mutations of INI1 in pediatric rhabdoid tumors of the central nervous system (Biegel et al, 1999), and have now documented germline mutations in patients with primary tumors of the brain and kidney. INI1 is a member of the SWIJSNF complex, one of several cell- cycle and ATP-dependent nucleosome remodeling complexes in mammalian cells. The SWTJSNF complex functions in both activation and repression of downstream target genes. In this proposal, we will define the spectrum of INI1 deletions and mutations in pediatric rhabdoid tumors of the brain, kidney and soft tissues. The frequency of inherited and de novo germline mutations in patients and their parents will be determined. Homozygous deletion of INI1 in chromosome band 22q 11.2 has been observed in 11 percent of tumors, whereas nonsense and frameshift mutations have been demonstrated in almost 50 percent of cases. In contrast, approximately 25 percent of primary tumors demonstrate alterations of the exon-intron 1 region of INI1 that result in absent INI1 gene expression. We propose that genomic rearrangements in this region or hypermethylation of CpG dinucleotides could decrease INI1 expression. Monosomy or deletion of the other chromosome 22 would thus result in homozygous inactivation of INI1, leading to tumor formation. The specificity of INTl mutations for rhabdoid tumors will also be addressed in this program, with particular emphasis on evaluating a larger series of medulloblastoma-primitive neuroectodermal tumors and choroid plexus carcinomas of the brain, as well as a series of pediatric rhabdomyosarcomas. These studies will lead to a better understanding of the role of INTl in the development of malignancy, improvements in determining diagnosis and prognosis for patients and their families, and ultimately, biologically based treatment strategies.