Identification of CCND3 and BYSL as candidate targets for the 6p21 amplification in diffuse large B-cell lymphoma
Identification of CCND3 and BYSL as candidate targets for the 6p21 amplification in diffuse large B-cell lymphoma
复制标题
DOI：
10.1158/1078-0432.ccr-05-1028
复制
发表时间：
2005-12-01
影响因子：
11.5
通讯作者：
Seto, M
中科院分区：
文献类型：
--
作者：
Kasugai, Y;Tagawa, H;Seto, M
目的：通过 DNA 扩增增加基因剂量是许多肿瘤的共同特征，并可能导致肿瘤促进基因的上调。我们最近对 66 例弥漫性大 B 细胞淋巴瘤进行全基因组、基于芯片的比较基因组杂交分析，发现在多达 17 例弥漫性大 B 细胞淋巴瘤中观察到 6p21 的基因组增益，其中 14 例具有低水平拷贝数增益，3 例具有高水平拷贝数增益（扩增）。 实验设计和结果：为了确定 6p21 扩增的靶基因，我们在基因组扩增区域构建了详细的扩增子图谱，其中借助基于高分辨率重叠群阵列的比较基因组杂交载玻片，该载玻片由连续有序的细菌人工染色体/P1 衍生的人工染色体克隆组成，覆盖整个 6p21 扩增区域 3 Mb。扩增的比对确定了包含 15 个基因的最小重叠 800 kb 片段。对患者样本和 SUDHL9 细胞系的基因进行定量表达分析表明，CCND3 和 BYSL（CCND3 基因座的 1.9 kb 端粒）是 6p21 基因组增益/扩增的靶标。 结论：虽然已知 t(6;14)(p21;q32) 会在 B 细胞恶性肿瘤中诱导 CCND3 异常过度表达，但我们能够证明CCND3 编码控制细胞周期调节 G(1)-S 期的细胞周期蛋白 D 家族成员蛋白，也可以成为基因组增益/扩增的目标。尽管 BYSL 在肿瘤发生方面的确切生物学作用仍有待确定，但通过基因组扩增过度表达 CCND3 可能会导致异常的细胞周期控制。
Purpose: Increases in gene dosage through DNA amplification represents a common feature of many tumors and can result in the up-regulation of tumor-promoting genes. Our recent genome-wide, array-based comparative genomic hybridization analysis of 66 cases of diffuse large B-cell lymphoma found that genomic gain of 6p21 was observed in as many as 17 cases, including 14 cases with low-level copy number gain and three cases with high-level copy number gains (amplifications).Experimental Design and Results: To identify the target gene(s) for 6p21 amplification, we constructed a detailed amplicon map at the region of genomic amplification with the aid of high-resolution contig array-based comparative genomic hybridization glass slides, consisting of contiguously ordered bacterial artificial chromosome/P1 -derived artificial chromosome clones covering 3 Mb throughout the 6p21 amplification region. Alignment of the amplifications identified a minimally overlapping 800 kb segment containing 15 genes. Quantitative expression analysis of the genes from both patient samples and the SUDHL9 cell line revealed that CCND3 and BYSL (1.9 kb telomeric to the CCND3 gene locus) are the targets of 6p21 genomic gain /amplification.Conclusions: Although it is known that t(6;14)(p21;q32) induces aberrant overexpression of CCND3 in B-cell malignancies, we were able to show that CCND3, which encodes the cyclin D family member protein that controls the G(1)-S phase of cell cycle regulation, can also be a target of genomic gain /amplification. Overexpression of CCND3 through genomic amplification is likely to lead to aberrant cell cycle control, although the precise biological role of BYSL with respect to tumorigenesis remains to be determined.