CHROMOSOMAL ABNORMALITIES IN MYELOMA AS DETECTED BY FISH

描述(改编自调查人员的摘要)：背景；多个 骨髓瘤(MM)是一种无法治愈的浆细胞恶性肿瘤。大多数调查人员认为 多发性骨髓瘤的进展和结果是特定基因改变的次要因素 恶性细胞的数量。14q32的易位被认为是遗传 MM的特征由常规细胞遗传学分析(CC)、其他和Dr。 Fonseca已经确定染色体异常的存在是 与不利结果相关的。腕长臂的结构异常 11号染色体(主要是易位)和13号染色体以及17号染色体的短臂 具有特殊的预后意义。然而，CC充满了许多困难 包括无法检测到非增殖细胞的异常。 荧光原位杂交(FISH)可以检测染色体异常 在间期细胞中。鱼类的预后意义尚不清楚。 初步数据表明，FISH检测到的染色体异常是 也很有意义。对多发性骨髓瘤细胞遗传机制的认识 增殖、疾病进展和结果对最终 战胜疾病。此外，这些异常可能会识别 MM的不同生物学亚群。 假设：1)特定的染色体结构和数量异常将 对MM患者的预后有意义(总存活率和事件 自由生存)。2)易位会导致基因过度表达，如 通过RNA分析(逆转录聚合酶链式反应， RT-PCR)和免疫组织化学染色。3)这些染色体异常会有 与已知生物学和预后因素的相关性。4)具体 治疗开始后两年可能导致染色体异常 在与治疗相关的骨髓发育不良或急性白血病(TMDS/AML)的发展中。 目标：1)确定频率和预后意义(总体 14q32之间易位的存活率和无事件存活率 供体染色体(11q13、4q16.3、16q23)、缺失(13q和17p13)和 染色体数目异常(第6、7、9、11、15、17号染色体)。2) 特定染色体易位的存在与由此导致的 RT-PCR(细胞周期蛋白D1、FGFR3、MMSET和c-maf)基因的过度表达 免疫组织化学(仅限细胞周期蛋白D1)。3)相关的染色体异常 肿瘤生物标志物(浆细胞标记指数、B-2微球蛋白、 C反应蛋白、可溶性IL-6受体、脱氧核糖核酸含量S期、脱氧核糖核酸异倍体 和浆母细胞形态)。4)评估特定的染色体 与骨髓营养不良和治疗相关的白血病相关的异常 将这些发现与TMDS/AML的临床发展联系起来。 材料和方法；检测染色体异常，他将执行 利用基因座特异性和染色体特异性探针的双色FISH 为E9487(相关辅助实验室)采集250例患者样本 试验到临床试验E9486)。为了准确鉴定单型浆细胞，他 将鱼与细胞质免疫球蛋白的荧光染色结合起来。 此外，他还将进行RT-PCR以进行RNA分析和免疫组织化学 蛋白过表达(细胞周期蛋白D1)。他将进行生物关联 并进行总体生存和无事件生存 根据有无特定异常进行分析。 还将使用多变量模型对变量进行研究，以测试它们 独立预测者。

DESCRIPTION (adapted from the investigator's abstract): Background; Multiple myeloma (MM) is an incurable plasma cell malignancy. Most investigators believe that progression and outcome in MM is secondary to specific genetic alterations of the malignant cells. Translocations at 14q32 are thought to be the genetic hallmark of MM. By conventional cytogenetic analysis (CC), others and Dr. Fonseca have determined that the presence of chromosomal abnormalities is associated with an adverse outcome. Structural abnormalities of the long arm of chromosomes 11 (mostly translocations), and 13 and the short arm of 17 have special prognostic significance. However, CC is fraught with many difficulties including inability to detect abnormalities in non-proliferating cells. Fluorescent in situ hybridization (FISH) can detect chromosomal abnormalities in interphase cells. The prognostic significance of FISH is not yet known. Preliminary data suggest that chromosomal abnormalities as detected by FISH are of significance as well. Understanding the genetic mechanisms of MM cell proliferation, disease progression and outcome is important to eventually overcoming the disease. Furthermore these abnormalities may identify biologically different subgroups of MM. Hypothesis: 1) Specific chromosomal structural and numerical abnormalities will have prognostic significance in patients with MM (overall survival and event free survival). 2) Translocations will result in gene overexpression as detected by RNA analysis (reverse transcriptase polymerase chain reaction, TR-PCR) and immunohistochemistry. 3) These chromosomal abnormalities will have correlations with known biological and prognostic factors. 4) Specific chromosomal abnormalities at two years after initiation of treatment may result in development of therapy-related myelodysplasia or acute leukemia (tMDS/AML). Objectives: 1) Determine the frequency and prognostic significance (overall survival and event free survival) of translocations between 14q32 and other donors chromosomes (11q13, 4q16.3, 16q23), deletions (13q and 17p13) and numerical chromosomal abnormalities (chromosomes 6, 7, 9, 11, 15,17). 2) Correlate the presence of specific chromosomal translocations with resulting gene overexpression by RT-PCR (cyclin D1, FGFR3, MMSET, and c-maf) and immunohistochemistry (cyclin D1 only). 3) Correlate chromosomal abnormalities with tumor biological markers (plasma cell labeling index, B-2 microglobulin, C-reactive protein, soluble IL-6 receptor, DNA content S-phase, DNA aneuploidy, and plasmablastic morphologic). 4) Assess for specific chromosomal abnormalities associated to myelodysphasia and therapy related leukemia and relate these findings to clinical development of tMDS/AML. Material and Methods; To detect chromosomal abnormalities he will perform dual-color FISH using locus-specific and chromosome-specific probes on archival samples of 250 patients collected for E9487 (associated ancillary laboratory trial to clinical trial E9486). To precisely identify monotypic plasma cells he will couple FISH with fluorescent staining for the cytoplasmic immunoglobulin. Additionally, he will do RT-PCR for RNA analysis and immunohistochemistry for protein overexpression (cyclin D1). He will perform biological correlations with other markers, and perform an overall survival and event free survival analysis according to the presence or absence of specific abnormalities. Variables will also be studied using a multiple-variable model to test them as independent predictors.