Genetics of Pediatric Rhabdoid Tumors

描述：（改编自研究者摘要）横纹肌样瘤是一种 快速致命的恶性肿瘤，通常出现在头两年的 生活最常见的表现部位是大脑和肾脏。我们和 其他人则结合细胞遗传学和分子研究来定义一种 在22q11.2的关键区域，包含横纹肌样肿瘤抑制基因。 最近，Versteege等（1998）报道了hSNF 5/INI 1作为一个候选基因， 肾和肾外横纹肌样瘤。我们鉴定了生殖细胞和体细胞 儿童中枢神经系统横纹肌样瘤中INI 1基因突变的研究 （Biegel等，1999），并且现在已经记录了患者中的生殖系突变。 患有脑部和肾脏的原发性肿瘤。INI 1是SWIJSNF的成员 复合物，细胞周期和ATP依赖的核小体重塑之一 哺乳动物细胞中的复合物。SWTJSNF复合体在两种激活中起作用 和抑制下游靶基因。在本提案中，我们将定义 儿童横纹肌样瘤中INI 1缺失和突变谱 大脑、肾脏和软组织。遗传和新生生殖系的频率 将确定患者及其父母的突变。纯合缺失 在11%的肿瘤中观察到染色体带22q11.2中的INI 1， 而无义和移码突变已经在近50个 %的案件。相反，大约25%的原发性肿瘤 显示INI 1的外显子-内含子1区域的改变， 缺乏INI 1基因表达。我们认为，基因组重排，在这一点上， 区域或CpG二核苷酸甲基化可降低INI 1的表达。 因此，另一条染色体22的单体性或缺失将导致纯合性。 INI 1失活，导致肿瘤形成。INT 1的特异性 横纹肌样瘤的突变也将在该计划中得到解决， 特别强调评价一个更大的系列髓母细胞瘤-原始 脑神经外胚层肿瘤和脉络丛癌，以及 一系列儿童横纹肌肉瘤这些研究将导致更好的 了解INT 1在恶性肿瘤发展中的作用， 在确定患者的诊断和预后方面的改进及其 家庭，最终，基于生物学的治疗策略。

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.