Copy-Neutral Loss of Heterozygosity at the p53 Locus in Carcinogenesis of Esophageal Squamous Cell Carcinomas Associated with p53 Mutations
Copy-Neutral Loss of Heterozygosity at the p53 Locus in Carcinogenesis of Esophageal Squamous Cell Carcinomas Associated with p53 Mutations
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DOI：
10.1158/1078-0432.ccr-10-1996
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发表时间：
2011-04-01
影响因子：
11.5
通讯作者：
Maehara, Yoshihiko
中科院分区：
文献类型：
--
作者：
Saeki, Hiroshi;Kitao, Hiroyuki;Maehara, Yoshihiko
目的：p53位点的洛缺失与食管鳞状细胞癌的发生有关。本研究的目的是确定潜在的机制，导致洛周围的p53基因位点在其canceration.Experimental设计：我们调查了10个食管癌细胞系和91个手术切除标本，检查他们的洛在p53基因位点上的17号染色体。结果：p53基因位点的突变与洛缺失密切相关（P <0.01），p53基因的突变与杂合性缺失密切相关（P < 0.01）。虽然发现4个细胞系是p53突变纯合的，但CGH未检测到p53位点的洛。在两个p53突变的癌细胞系和五个p53突变/洛癌标本中，通过FISH分析，两个细胞系和四个标本在p53位点没有表现出明显的拷贝数丢失。SNP-CGH分析，它可以确定DNA拷贝数和检测拷贝中性洛，表明没有拷贝数变化的LOH是由整个或大的染色体改变引起的。结论：p53基因突变的食管鳞状细胞癌中观察到洛没有拷贝数变化。我们的数据表明，拷贝中性洛丢失发生的结果，染色体不稳定可能是失活的完整的等位基因在食管鳞状细胞癌与p53突变相关的主要机制。临床癌症研究; 17（7）; 1731-40。(C)2011年AACR。
Purpose: LOH at the p53 locus has been reported to be associated with esophageal squamous cell carcinogenesis. The aim of this study is to identify potential mechanisms resulting in LOH around the p53 locus in its carcinogenesis.Experimental Design: We investigated 10 esophageal cancer cell lines and 91 surgically resected specimens, examining them for LOH at the p53 locus on chromosome 17. We examined the p53 gene by using microsatellite analysis, comparative genomic hybridization (CGH), FISH, and single-nucleotide polymorphism-CGH (SNP-CGH).Results: In an analysis of specimens by microsatellite markers, a close positive correlation was found between p53 mutations and LOH at the p53 locus (P < 0.01). Although four cell lines were found to be homozygous for p53 mutations, LOH at the p53 locus was not detected by CGH. Among two p53 mutant cancer cell lines and five p53 mutant/LOH cancer specimens analyzed by FISH, both the cell lines and four of the specimens exhibited no obvious copy number loss at the p53 locus. SNP-CGH analysis, which allows both determination of DNA copy number and detection of copy-neutral LOH, showed that LOHs without copy number change were caused by whole or large chromosomal alteration.Conclusions: LOH without copy number change at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. Our data suggest that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutation. Clin Cancer Res; 17(7); 1731-40. (C) 2011 AACR.