Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma
Definition and characterization of a region of 1p36.3 consistently deleted in neuroblastoma
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DOI：
10.1038/sj.onc.1208306
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发表时间：
2005-04-14
期刊：
影响因子：
8
通讯作者：
Brodeur, GM
中科院分区：
文献类型：
--
作者：
White, PS;Thompson, PM;Brodeur, GM
来自原发肿瘤和细胞系的大量基因组和功能证据表明，在相当大比例的人类神经母细胞瘤中，染色体远端1p的一致区域被删除，这表明该区域含有一个或多个肿瘤抑制基因。为了系统准确地确定神经母细胞瘤中1p缺失的位置和程度，我们对737例原发性神经母细胞瘤进行了等位基因缺失研究，并对46例神经母细胞瘤细胞系进行了基因型分析。总之，结果确定了1p36.3内的单个区域，该区域在25%的肿瘤和87%的细胞系中一致被删除。两名神经母细胞瘤患者的远端1p36存在与肿瘤定义区域重叠的构象缺失。肿瘤来源的缺失和体质来源的缺失共同定义了D1S2795和D1S253之间的最小一致缺失区域（SRD）。184例1p缺失的肿瘤中，除1例外，其余均缺失1p36.3 SRD。物理图谱和DNA测序确定SRD最小跨度估计为729 kb。基因组内容和序列分析鉴定出15个已鉴定基因、9个未鉴定基因和6个预测基因。研究了其中21个基因在多种正常组织中的RNA表达谱。SHREW1和KCNAB2基因都具有组织限制性表达模式，包括在神经系统中的表达。此外，一个与染色质重塑相关蛋白具有强同源性的新基因（CHD5）主要在神经组织中表达。总之，这些结果表明，一个或多个参与神经母细胞瘤肿瘤发生或肿瘤进展的基因可能包含在该区域。
Substantial genomic and functional evidence from primary tumors and cell lines indicates that a consistent region of distal chromosome 1p is deleted in a sizable proportion of human neuroblastomas, suggesting that this region contains one or more tumor suppressor genes. To determine systematically and precisely the location and extent of 1p deletion in neuroblastomas, we performed allelic loss studies of 737 primary neuroblastomas and genotype analysis of 46 neuroblastoma cell lines. Together, the results defined a single region within 1p36.3 that was consistently deleted in 25% of tumors and 87% of cell lines. Two neuroblastoma patients had constitutional deletions of distal 1p36 that overlapped the tumor-defined region. The tumor- and constitutionally-derived deletions together defined a smallest region of consistent deletion (SRD) between D1S2795 and D1S253. The 1p36.3 SRD was deleted in all but one of the 184 tumors with 1p deletion. Physical mapping and DNA sequencing determined that the SRD minimally spans an estimated 729 kb. Genomic content and sequence analysis of the SRD identified 15 characterized, nine uncharacterized, and six predicted genes in the region. The RNA expression profiles of 21 of the genes were investigated in a variety of normal tissues. The SHREW1 and KCNAB2 genes both had tissue-restricted expression patterns, including expression in the nervous system. In addition, a novel gene (CHD5) with strong homology to proteins involved in chromatin remodeling was expressed mainly in neural tissues. Together, these results suggest that one or more genes involved in neuroblastoma tumorigenesis or tumor progression are likely contained within this region.