George R E, Kenyon R, McGuckin A G, Kohl N, Kogner P, Christiansen H, Pearson A D, Lunec J
Cancer Research Unit, Newcastle University Medical School, University of Newcastle upon Tyne, U.K.
Eur J Cancer. 1997 Oct;33(12):2037-42. doi: 10.1016/s0959-8049(97)00206-2.
Previous studies have revealed that the MYCN gene spans approximately 7kb, while the amplicon has been estimated to be 100 kb to 1 Mb long [1-3]. This implies that several other genes may be present on the MYCN amplicon. Such co-amplified genes could contribute to the malignant phenotype and might provide an explanation for why not all patients with MYCN amplification have a poor outcome. We investigated 7 neuroblastoma cell lines and 167 primary tumours for the co-amplification of candidate genes known to be present near the MYCN locus: ornithine decarboxylase, ribonucleotide reductase, syndecan-1 and a DEAD box protein gene, DDX1. We also investigated further the pG21 expressed sequence previously reported to be co-amplified with MYCN. No co-amplification with the first 3 genes was found in any of the cell lines or tumour samples. DDX1 was found to be amplified along with MYCN in 4/6 (67%) cell lines and 18/38 (47%) of the MYCN amplified tumours. No amplification of DDX1, ODC1, RRM2 or syndecan-1 was found in the absence of MYCN amplification. DDX1 co-amplification was observed to occur mainly in stage 4 or 4S patients. With the exclusion of those with 4S disease, patients with DDX1 co-amplification had a significantly shorter mean (+/- SE) disease-free interval (4.1 +/- 1.4, n = 8 months) compared with patients with MYCN amplification alone (19.6 +/- 4.5, n = 17) (P = 0.04, Welch's unpaired t-test). The pG21 sequence was identical to part of the DDX1 gene. These observations indicate that there is at least 1 other gene co-amplified with MYCN in a proportion of cases and that those patients with DDX1 co-amplification tend to relapse more quickly. It also implies that the MYCN amplicon is of varied size and/or position relative to the MYCN gene.
先前的研究表明，MYCN基因跨度约为7kb，而扩增子估计长度为100kb至1Mb [1-3]。这意味着MYCN扩增子上可能存在其他几个基因。这些共扩增基因可能导致恶性表型，并且可能解释为什么并非所有MYCN扩增的患者预后都差。我们研究了7种神经母细胞瘤细胞系和167例原发性肿瘤，以检测已知位于MYCN基因座附近的候选基因的共扩增情况：鸟氨酸脱羧酶、核糖核苷酸还原酶、多配体蛋白聚糖-1和一个DEAD盒蛋白基因DDX1。我们还进一步研究了先前报道的与MYCN共扩增的pG21表达序列。在任何细胞系或肿瘤样本中均未发现与前3个基因的共扩增。在4/6（67%）的细胞系和18/38（47%）的MYCN扩增肿瘤中发现DDX1与MYCN一起扩增。在没有MYCN扩增的情况下，未发现DDX1、ODC1、RRM2或多配体蛋白聚糖-1的扩增。观察到DDX1共扩增主要发生在4期或4S期患者中。排除4S期疾病患者后，与仅MYCN扩增的患者（19.6 +/- 4.5，n = 17）相比，DDX1共扩增的患者平均（+/- SE）无病间期显著缩短（4.1 +/- 1.4，n = 8个月）（P = 0.04，韦尔奇非配对t检验）。pG21序列与DDX1基因的一部分相同。这些观察结果表明，在一部分病例中至少有1个其他基因与MYCN共扩增，并且那些DDX1共扩增的患者往往复发更快。这也意味着MYCN扩增子相对于MYCN基因的大小和/或位置各不相同。
