MOLECULAR GENETICS OF CHROMOSOME 13 DELETIONS

描述：（申请人的描述） MM不太了解。然而，这项计划资助的研究 已经揭示，13号染色体缺失是主要的不利特征， 患者结局。仔细检查我们广泛的细胞遗传学数据库， 超过1000名患者，已经确定13 q14是最常见的受累带 在13号染色体缺失的人群中（超过90%）。不像 常规的中期分析表明， 不超过20%，间期FISH与RB 1基因在高达50 %，我们的初步数据与12个分子探针跨越整个 16名患者中有14名（87%）发现13号染色体q臂缺失。在所有 例缺失涉及标记D13 S272，这是唯一的异常 在三个案例中。到目前为止，缺失模式独立于先验的程度， 疗法骨髓瘤特异性肿瘤抑制基因的研究进展 基因，这个项目将追求两个具体目标。(1)使用三重颜色 间期FISH，我们将详细定义最小缺失区域（S） 新诊断和既往治疗患者细胞中的13号染色体 进入项目1和2的临床试验。连续采样将允许 研究13号染色体缺失的预期演变， 疾病进展。(2)根据删除频率和删除 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，阐明它们在 骨髓瘤发展，最终目标是开发基于基因的疗法。

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.