GENETICS OF PEDIATRIC RHABDOID TUMORS

横纹肌样瘤是一种迅速致死的恶性肿瘤，通常表现为 在生命的头两年。肿瘤可能出现在不同的 身体的各个部位，但最常见于大脑和 肾脏。据报道，一些患者既有初级中枢神经系统疾病，也有 神经系统恶性肿瘤和原发肾脏横纹肌样瘤， 这表明这些肿瘤有共同的分子病因学。我们有 报道称，脑部横纹肌样瘤，或横纹肌样肌瘤的变种 肿瘤被称为非典型畸胎样瘤，其特征是 22号染色体单体或缺失。结合细胞遗传学和 分子研究已经被用来定义一个关键区域 22q11.2含有横纹肌样肿瘤基因。我们 假设肿瘤的纯合缺失或失活 该区域内的抑制子基因负责该区域的发育 儿童中枢神经系统肾脏横纹肌样瘤， 和肾外组织。该轨迹的最小临界区 小于500kb，并跨越免疫球蛋白之间的区域 基因座和bcr基因。我们已经构建了一个连续的重叠 一组宇宙体和细菌人工染色体(BAC) 横跨横纹肌样瘤的临界区。宇宙星和宇宙飞船将会 用于分离横纹肌样瘤基因的候选cDNA 大规模基因组序列分析与外显子相结合 诱捕方法。然后对候选基因进行基因组分析。 匹配的m=正常和肿瘤组织中的变化和突变 横纹肌样瘤患者。我们将确定基因组 基因结构，并分析其在正常组织和肿瘤中的表达 纸巾。横纹肌样瘤基因的鉴定将是一个主要的 对设计敏感的诊断分析的贡献，以及 改进了治疗方案。

Rhabdoid tumor is a rapidly fatal malignancy which generally presents in the first two years of life. The tumors may present in various locations of the body, but are most often seen in the brain and Kidney. Some patients have been reported with both a primary central nervous system malignancy and a primary renal rhabdoid tumor, suggesting that the tumors have a common molecular etiology. We have reported that rhabdoid tumor of the brain, or a variant of rhabdoid tumor referred to as a atypical teratoid tumor, is characterized by monosomy or deletion of chromosome 22. Combined cytogenetic and molecular studies have been used to define a critical region in 22q11.2 which we proposed contains a rhabdoid tumor locus. We hypothesize that homozygous deletion or inactivation of a tumor suppressor gene within this region is responsible for the development of pediatric rhabdoid tumors of the central nervous system kidney, and extra-renal tissues. The minimal critical region for this locus is less than 500 kb, and spans the region between the immunoglobulin loci and the BCR gene. We have constructed a contiguous overlapping set of cosmids and bacterial artificial chromosomes (BACs) which spans the rhabdoid tumor critical region. The cosmids and BACs will be used to isolate candidate cDNAs for the rhabdoid tumor gene by a combination of large scale genomic sequence analysis and exon trapping methods. Candidate genes will then be analyzed for genomic alterations and mutations in matched m=normal and tumor tissue from patients with rhabdoid tumors. We will determine the genomic structure of the gene, and analyze its expression in normal and tumor tissues. Identification of the rhabdoid tumor gene will be a major contribution towards the design of sensitive diagnostic assays, and improved treatment protocols.