MULTIPLE POLYMORPHISMS, BUT NO MUTATIONS, IN THE WAF1/CIP1 GENE IN HUMAN BRAIN-TUMORS
MULTIPLE POLYMORPHISMS, BUT NO MUTATIONS, IN THE WAF1/CIP1 GENE IN HUMAN BRAIN-TUMORS
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DOI：
10.1038/bjc.1995.491
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发表时间：
1995-11-01
影响因子：
8.8
通讯作者：
VONDEIMLING, A
中科院分区：
文献类型：
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作者：
KOOPMANN, J;MAINTZ, D;VONDEIMLING, A
细胞周期蛋白激酶抑制剂 WAF1/CIP1（也称为 CDKN1）可介导 p53 诱导的细胞周期停滞以响应 DNA 损伤。这一特性使其成为 p53 相关肿瘤抑制基因的有吸引力的肿瘤抑制候选者。为了研究 WAF1/CIPI 在原发性人类脑肿瘤发病机制中的作用，我们在 158 个具有代表性的脑肿瘤和相应的血液样本中进行了单链构象多态性 (SSCP) 分析和基因外显子 2 的直接测序。此外，所有肿瘤都检查了 p53 基因外显子 5-8 的突变。 WAF1/CIP1分析显示多种多态性，最丰富的是密码子31处的AGC-->AGA（Ser-->Arg），等位基因频率为8.5%。不太常见的多态性包括密码子 25 处的 GTG-->GGG (Val-->Gly)、密码子 64 处的 GCC-->ACC (Ala-->Thr)、密码子 32 处的 CGC-->CTC (Arg-->Leu)、密码子 14 处的 GGC-->AGC (Gly-->Ser) 和密码子处的 GCG-->GTG (Ala-->Val) 39 个，每个等位基因频率为 0.3%。这些多态性均位于外显子 2 的保守区域。在 157 名健康对照组中也发现了其中两个多态性，表明 WAF1/CIP1 多态性不会诱发癌症。我们系列中的肿瘤均未显示出 WAF1/CIP1 体细胞突变。还分析了所有样品 WAF1/CIP1 基因座区域 6 号染色体短臂杂合性的丢失。仅在一名胶质母细胞瘤患者中观察到等位基因丢失。在 158 个肿瘤中的 22 个中发现了 p53 基因突变。未发现 WAF1/CIP1 基因多态性、p53 突变与组织病理学肿瘤类型之间存在关联。我们的数据表明WAF1/CIP1突变可能不参与原发性人脑肿瘤的形成。
The cyclin kinase inhibitor WAF1/CIP1, also termed CDKN1, mediates p53-induced cell cycle arrest in response to DNA damage. This property makes it an attractive tumour-suppressor candidate for a p53-associated tumour-suppressor gene. In order to investigate the role of WAF1/CIPI in the pathogenesis of primary human brain tumours we performed single-stranded conformation polymorphism (SSCP) analysis and direct sequencing of exon 2 of the gene in a representative series of 158 brain tumours and corresponding blood samples. In addition, all tumours were examined for mutations in exons 5-8 of the p53 gene. Analysis of WAF1/CIP1 revealed multiple polymorphisms, the most abundant being AGC-->AGA (Ser-->Arg) at codon 31 with an allele frequency of 8.5%. Less common polymorphisms included GTG-->GGG (Val-->Gly) at codon 25, GCC-->ACC (Ala-->Thr) at codon 64, CGC-->CTC (Arg-->Leu) at codon 32, GGC-->AGC (Gly-->Ser) at codon 14 and GCG-->GTG (Ala-->Val) at codon 39 each with an allele frequency of 0.3%. These polymorphisms were all located in a conserved region of exon 2. Two of the polymorphisms were also seen in a group of 157 healthy controls indicating that WAF1/CIP1 polymorphisms do not predispose to cancer. None of the tumours included in our series showed a somatic mutation in WAF1/CIP1. All samples were also analysed for loss of heterozygosity on the short arm of chromosome 6 in the region of the WAF1/CIP1 locus. Allelic loss was observed in only one patient with a glioblastoma. Mutations in the p53 gene were found in 22 of 158 tumours. No association was found between any polymorphism of the WAF1/CIP1 gene, p53 mutations and histopathological tumour type. Our data indicate that WAF1/CIP1 mutations are probably not involved in the formation of primary human brain tumours.