p73 at chromosome 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent
p73 at chromosome 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent
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DOI：
10.1038/sj.onc.1202390
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发表时间：
1999-01-28
期刊：
影响因子：
8
通讯作者：
Nakagawara, A
中科院分区：
文献类型：
--
作者：
Ichimiya, S;Nimura, Y;Nakagawara, A
p73是一个新的p53家族成员，是最近发现的候选神经母细胞瘤（NBL）抑制基因，定位在染色体1p36.33，被发现在细胞系中抑制生长和诱导凋亡。为了验证p73是NBL抑制基因的假设，我们分析了原发人NBL中的p73基因，在包括92例MS肿瘤的信息病例中，有19%（28/151）观察到p73的杂合性缺失（LOH）。p73 LOH的高频率与散发性NBLs（9%比34%，P < 0.001）、N-myc扩增（10%比71%，P < 0.001）和晚期（14%比28%，P < 0.05）显著相关。RT-PCR方法在134例低水平NBLs中仅46例（34%）检测到p73 α和p73 β转录本，而在相同条件下大多数乳腺癌和结直肠癌中均可检测到p73 α和p73 β转录本。他们发现p73 LOH与其表达水平之间没有相关性（P >.1）。我们在140个NBLs中发现两个突变，一个是体细胞的，一个是种系的，这导致p73 c端区域的氨基酸替换，这可能会影响转激活功能，尽管在相同的肿瘤样本中，没有观察到p53基因突变。这些结果表明，p73基因的等位基因丢失可能是NBL肿瘤发生后发生的事件。然而，p73在原发性NBLs中很少发生突变，并且可能很难以经典的Knudson方式作为肿瘤抑制因子。
p73, a novel p53 family member, is a recently identified candidate neuroblastoma (NBL) suppressor gene mapped at chromosome 1p36.33 and was found to inhibit growth and induce apoptosis in cell lines. To test the hypothesis that p73 is a NBL suppressor gene, we analysed the p73 gene in primary human NBLs, Loss of heterozygosity (LOH) for p73 was observed in 19% (28/151) of informative cases which included 92 mass-screening (MS) tumors. The high frequency of p73 LOH was significantly associated with sporadic NBLs (9% vs 34%, P < 0.001), N-myc amplification (10% vs 71%, P < 0.001), and advanced stage (14% vs 28%, P < 0.05), Both p73 alpha and p73 beta transcripts were detectable in only 46 of 134 (34%) NBLs at low levels by RT-PCR methods, while they were easily detectable in most breast cancers and colorectal cancers under the same conditions. They found no correlation between p73 LOH and its expression levels (P > 0.1), We found two mutations out of 140 NBLs, one somatic and one germline, which result in amino acid substitutions in the C-terminal region of p73 which may affect transactivation functions, though, in the same tumor samples, no mutation of the p53 gene was observed as reported previously. These results suggest that allelic loss of the p73 gene may be a later event in NBL tumorigenesis. However, p73 is infrequently mutated in primary NBLs and may hardly function as a tumor suppressor in a classic Knudson's manner.