MOLECULAR GENETICS OF CHROMOSOME 13 DELETIONS

描述：(申请者的描述)细胞和分子遗传学 MM很少被理解。然而，这项计划资助的研究 已经揭示了13号染色体的缺失是 病人结局。详细审查我们广泛的细胞遗传学数据库，以及更多 1000多名患者，已确定13q14是最常见的受累波段 在13号染色体缺失的患者中(超过90%)。不像 常规中期分析显示13号染色体缺失 不超过20%和间期FISH与RB1基因在高达50% 百分比，我们的初步数据有12个分子探测器，跨越整个 13号染色体Q臂在14/16(87%)患者中发现缺失。总而言之， 6例中，缺失涉及标记D13S272，这是唯一的异常 在三个案例中。到目前为止，缺失模式与先前的程度无关 心理治疗。向鉴定骨髓瘤特异性肿瘤抑制因子的目标迈进 基因，这个项目将追求两个具体目标。(1)使用三色 间期FISH，我们将详细定义最小缺失区(S) 新诊断和既往治疗患者的细胞中的13号染色体 进入项目1和2的临床试验。连续抽样将允许 13号染色体缺失的预期进化研究 疾病的发展。(2)根据删除频率和删除情况 与临床病程的相关性(项目1和2；SCID-HU读数，项目5) 我们将定位克隆受影响的基因(S)，阐明它们在 骨髓瘤开发，最终目标是开发基于基因的治疗方法。

DESCRIPTION: (Applicant's Description) The cellular and molecular genetics of MM are poorly understood. However, studies supported by this program grant have revealed that chromosome 13 deletion is the major adverse feature for patient outcome. Scrutiny of our extensive cytogenetic database, with more than 1000 patients, has identified 13q14 as the most frequently involved band among those with chromosome 13 deletions (greater than 90 percent). Unlike conventional metaphase analyses which demonstrate chromosome 13 deletions in no more than 20 percent and interphase FISH with the RB1 gene in up to 50 percent, our preliminary data with 12 molecular probes spanning the entire chromosome 13 q-arm revealed deletions in 14/16 (87 percent) patients. In all cases, the deletions involved the marker D13S272, which was the sole anomaly in three cases. So far, deletion patterns were independent of extent of prior therapy. Toward the goal of identifying myeloma specific tumor suppressor genes, this project will pursue two specific aims. (1) Using triple color interphase FISH, we will define in detail the minimal deleted region(s) of chromosome 13 in cells from newly diagnosed and previously treated patients entered into clinical trials of Projects 1 and 2. Serial sampling will permit investigation of anticipated evolution in chromosome 13 deletions during disease progression. (2) On the basis of both deletion frequency and deletion relatedness to clinical course (Project 1 and 2; SCID-hu readout, Project 5), we will positional clone the affected gene(s), elucidate their function in myeloma development, with the ultimate goal to develop gene-based therapies.