Molecular and transcriptional characterization of the novel 17p11.2-p12 amplicon in multiple myeloma
Molecular and transcriptional characterization of the novel 17p11.2-p12 amplicon in multiple myeloma
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DOI：
10.1002/gcc.20494
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发表时间：
2007-12-01
影响因子：
3.7
通讯作者：
Neri, Antonino
中科院分区：
文献类型：
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作者：
Fabris, Sonia;Todoerti, Katia;Neri, Antonino
多发性骨髓瘤(MM)是一种克隆性骨髓浆细胞的恶性肿瘤，其特征是基因组高度不稳定，随着疾病的进展而增加。我们在这里描述了位于17p11.2-p12的基因组扩增，这是一个以大量低拷贝重复为特征的不稳定染色体区域，已被证明在几种基因组疾病和实体肿瘤的扩增中介导了缺失和复制。SNP微阵列分析在KMS-26骨髓瘤细胞系中检测到与5Mb相似的17p11.2-p12扩增区域。进一步的荧光原位杂交图谱显示了两条未知的扩增染色体和一种复杂的17号染色体重排模式。在一个专有的骨髓瘤细胞系数据库中的转录图谱分析发现，KMS-26扩增区有12个显著高表达的基因，包括TNFRSF13B/TACI、COPS3和NCOR1。在包括141个浆细胞癌原发瘤的数据库中，对它们的表达水平的评估显示，在13名患者中，至少有一个基因显著过度表达。对这些患者的FISH分析发现，一例多发性骨髓瘤携带3.8Mb扩增区域，两例多发性硬化症患者具有特定涉及TACI基因的增益。有趣的是，在KMS-26中发现了位于17p13.1的TP53的完全失活，而在三个携带增益/扩增的患者中有两个可识别出单等位基因丢失。我们的数据表明，与实体瘤相似，MM中17p11.2-p12区域的扩增/获得可能由该区域存在的重复序列所介导，并可能为定义新的候选骨髓瘤相关基因提供洞察力。
Multiple myeloma (MM) is a malignancy of clonal bone marrow plasma cells characterized by a high genomic instability increasing with disease progression. We describe here a genomic amplification at 17p 11.2-p 12, an unstable chromosomal region characterized by a large number of low-copy repeats, which have been proven to mediate deletion and duplication in several genomic disorders and amplifications in solid tumors. An similar to 5 Mb 17p11.2-p12 amplified region was detected in the KMS-26 myeloma cell line by SNP microarray analysis. Further fluorescence in situ hybridization mapping showed two unidentified amplified chromosomes as well as a complex pattern of rearranged chromosomes 17. The analysis of transcriptional profiles in a proprietary database of myeloma cell lines identified 12 significantly overexpressed genes in the KMS-26 amplified region, including TNFRSF13B/TACI, COPS3, and NCOR1. The evaluation of their expression levels in a database including 141 plasma cell dyscrasia primary tumors showed a significant overexpression of at least one gene in 13 patients. FISH analyses of these patients identified one MM carrying a 3.8 Mb amplified region and two MMs with gains specifically involving the TACI locus. Interestingly, the complete inactivation of TP53 at 17p 13.1 was found in the KMS-26, whereas a monoallelic loss was identifiable in two of the three patients carrying gain/amplification. Our data suggest that, similarly to solid tumors, amplification/gain of the 17p 11.2-p 12 region in MM could be mediated by the presence of repeats located in this region and may provide insights for defining novel candidate myeloma-associated genes.