Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line
Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line
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DOI：
10.1038/sj.onc.1203786
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发表时间：
2000-08-31
期刊：
影响因子：
8
通讯作者：
Nakagawara, A
中科院分区：
文献类型：
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作者：
Ohira, M;Kageyama, H;Nakagawara, A
在许多人类癌症中经常观察到染色体Ip远端区域的杂合性丢失，其中可能存在肿瘤抑制基因，包括伴有MYCN扩增和预后不良的神经母细胞瘤（NBL）。我们首次在两个NBL细胞系NB-1和NB-C201（MASS-NB-SCH 1）中在1p36.2-p36.3的最小重叠区域内鉴定了标记D1 S244处的同源缺失区域，尽管我们的基因分型表明这两个细胞系可能来自相同的起源。制备了覆盖整个纯合缺失区域的800-kb PAC重叠群，并进行了部分测序（约60%）。缺失区域的估计长度为500 kb。到目前为止，我们已经鉴定了该区域内的sis基因，其中包括三个已知基因（DFF 45，PGD和CORT）以及在过去31/2年的研究过程中报道的三个其他基因（HDNB 1/UFD 2，KIAA 0591 F/KIF 1B-β和PEX 14）。这些基因包括与细胞凋亡、糖代谢、泛素-蛋白酶体途径、神经元微管相关运动分子和过氧化物酶体生物发生有关的基因。至少有三个基因（HDNB 1/UFD 2，KIAA 0591 F/KIF 1B-beta和PEX 14）在原发性神经母细胞瘤的有利亚群中以高水平差异表达，而在不利亚群中以低水平差异表达。尽管RT-PCR-SSCP分析显示这些基因突变频率很低，但由于IP远端区域被报道为印迹基因，这些差异表达基因可能是NBL抑制基因的新成员。纯合缺失区的全序列测定和基因预测将阐明该区域更详细的结构，并可能导致发现额外的候选基因。
Loss of heterozygosity of the distal region of chromosome Ip where tumor suppressor gene(s) might harbor is frequently observed in many human cancers including neuroblastoma (NBL) with MYCN amplification and poor prognosis. We have identified for the first time a homozygously deleted region at the marker D1S244 within the smallest region of overlap at 1p36.2-p36.3 in two NBL cell lines, NB-1 and NB-C201 (MASS-NB-SCH1), although our genotyping has suggested the possibility that both lines are derived from the same origin. The 800-kb PAC contig covering the entire region of homozygous deletion was made and partially sequenced (about 60%). The estimated length of the deleted region was 500 kb. We have, thus far, identified sis genes within the region which include three known genes (DFF45, PGD, and CORT) as well as three other genes which have been reported during processing our present project for the last 31/2 years (HDNB1/UFD2, KIAA0591F/KIF1B-beta, and PEX14). They include the genes related to apoptosis, glucose metabolism, ubiquitin-proteasome pathway, a neuronal microtubule-associated motor molecule and biogenesis of peroxisome. At least three genes (HDNB1/UFD2, KIAA0591F/KIF1B-beta, and PEX14) were differentially expressed at high levels in favorable and at low levels in unfavorable subsets of primary neuroblastoma. Since the Ip distal region is reported to be imprinted, those differentially expressed genes could be the new members of the candidate NBL suppressor, although RT-PCR-SSCP analysis has demonstrated infrequent mutation of the genes so far identified. Full-sequencing and gene prediction for the region of homozygous deletion would elucidate more detailed structure of this region and might lead to discovery of additional candidate genes.