Hu N, Huang J, Emmert-Buck M R, Tang Z Z, Roth M J, Wang C, Dawsey S M, Li G, Li W J, Wang Q H, Han X Y, Ding T, Giffen C, Goldstein A M, Taylor P R
Divisions of clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2001 Apr;7(4):883-91.
Esophageal squamous cell carcinoma (ESCC) is one of the most common fatal cancers worldwide, and north central China has some of the highest rates in the world. Previous studies from tumors in this area of China have shown high frequencies of allelic loss on chromosome 17p13-11, which includes the region where the TP53 gene is found. We examined 56 ESCC patients using single-strand conformation polymorphism and DNA sequencing to assess the frequency and spectrum of TP53 mutation and the association between allelic loss at microsatellite marker TP53 and TP53 mutations. Ninety-six % of cases were found to have at least one genetic alteration, including TP53 mutation (77%), allelic loss within the TP53 gene (73%), and/or loss of heterozygosity at the TP53 microsatellite marker (80%); 75% had two or more such alterations, including 59% with both a point mutation and an intragenic allelic loss ("two hits"). The majority of mutations observed were in exon 5, where the most common type of nucleotide substitution was a G:C-->A:T or C:G-->T:A transition, including half that occurred at CpG sites. Allelic loss was most commonly found in exon 4 but was very common in exon 5 as well. Taken together, the multiple genetic alterations of TP53 in this population at high risk for ESCC indicate that there is a very high degree of genetic instability in these tumors, that TP53 is a primary target for inactivation, and that this tumor suppressor gene plays a critical role in the carcinogenesis process for ESCC.
食管鳞状细胞癌（ESCC）是全球最常见的致命癌症之一，中国中北部地区的发病率位居世界前列。此前对中国该地区肿瘤的研究表明，17p13 - 11染色体上等位基因缺失频率较高，该区域包含TP53基因所在位置。我们使用单链构象多态性和DNA测序技术对56例ESCC患者进行检测，以评估TP53突变的频率和谱型，以及微卫星标记TP53处的等位基因缺失与TP53突变之间的关联。结果发现，96%的病例至少存在一种基因改变，包括TP53突变（77%）、TP53基因内等位基因缺失（73%）和/或TP53微卫星标记处杂合性缺失（80%）；75%的病例有两种或更多种此类改变，其中59%同时存在点突变和基因内等位基因缺失（“双打击”）。观察到的大多数突变位于外显子5，最常见的核苷酸替换类型是G:C→A:T或C:G→T:A转换，其中一半发生在CpG位点。等位基因缺失最常见于外显子4，但在外显子5中也很常见。综上所述，该ESCC高危人群中TP53的多种基因改变表明，这些肿瘤存在高度的遗传不稳定性，TP53是失活的主要靶点，并且该肿瘤抑制基因在ESCC的致癌过程中起关键作用。
