GENETICS OF PEDIATRIC RHABDOID TUMORS

小儿横纹肌样肿瘤的遗传学

• 批准号: 2796265
• 负责人: JACLYN A BIEGEL
• 金额: $ 24.43万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-13 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2796265
• 关键词: adolescence (12-20); brain neoplasms; cellular oncology; child (0-11); clinical research; computer assisted sequence analysis; cytogenetics; fluorescent in situ hybridization; genetic mapping; human subject; molecular oncology; neoplasm /cancer diagnosis; neoplasm /cancer genetics; northern blottings; nucleic acid sequence; pediatric neoplasm /cancer; plasmids; polymerase chain reaction; single strand conformation polymorphism; tumor suppressor genes

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.

色鹿肿瘤是一种迅速致命的恶性肿瘤，通常呈现 在生命的头两年。 肿瘤可能存在于各种 身体的位置，但最常在大脑中看到 肾。 据报道，有些患者是主要中央 神经系统恶性肿瘤和原发性肾横纹肌肿瘤， 表明肿瘤具有共同的分子病因。 我们有 报道大脑的横纹肌肿瘤或类横纹肌变异 肿瘤称为非典型霉菌肿瘤，其特征是 染色体22染色体或缺失。结合细胞遗传学和 分子研究已用于定义关键区域 我们提出的22q11.2包含色虫肿瘤基因座。 我们 假设纯合缺失或肿瘤失活 该区域内的抑制基因是造成发展的原因 中枢神经系统肾脏的小儿胸肌肿瘤， 和肾外组织。 该基因座的最小关键区域 小于500 kb，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 一组宇宙和细菌人造染色体（BAC） 跨性横纹肌肿瘤关键区域。 宇宙和BAC将 用于通过A分离出横纹肌肿瘤基因的候选cDNA 大规模基因组序列分析和外显子的组合 捕获方法。 然后将分析候选基因的基因组 匹配的M =正常组织和肿瘤组织的变化和突变 牙龈肿瘤的患者。 我们将确定基因组 基因的结构，并分析其在正常和肿瘤中的表达 组织。 色鹿肿瘤基因的鉴定将是主要的 为敏感诊断测定法设计的贡献，以及 改进的治疗方案。