Chromosomal Instability Associated with Global DNA Hypomethylation is Associated with the Initiation and Progression of Esophageal Squamous Cell Carcinoma
Chromosomal Instability Associated with Global DNA Hypomethylation is Associated with the Initiation and Progression of Esophageal Squamous Cell Carcinoma
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DOI：
10.1245/s10434-014-3818-z
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发表时间：
2014-12-01
影响因子：
3.7
通讯作者：
Maehara, Yoshihiko
中科院分区：
文献类型：
--
作者：
Kawano, Hiroyuki;Saeki, Hiroshi;Maehara, Yoshihiko
背景整体DNA低甲基化与染色体不稳定性增加有关，并在肿瘤发生中起重要作用。长散布核元件-1（LINE-1）元件的甲基化状态是全局DNA甲基化的有用替代标记。尽管LINE-1低甲基化被认为是一个预后不良的标志物，但LINE-1甲基化水平与食管鳞状细胞癌（ESCC）中抑癌基因突变、染色体不稳定性和临床意义的相关性仍不清楚。采用亚硫酸氢盐焦磷酸测序法对105例ESCC患者的肿瘤组织和相应的正常食管粘膜进行了LINE-1甲基化水平的定量分析。PCR直接测序法检测p53基因第2 ~ 10外显子突变。采用单核苷酸多态性阵列比较基因组杂交分析方法评价染色体不稳定性。食管鳞癌组织中LINE-1甲基化水平显著低于正常食管黏膜组织。食管正常粘膜LINE-1甲基化水平与研究对象吸烟和饮酒均呈显著负相关。LINE-1低甲基化与食管鳞癌的淋巴结转移、淋巴管浸润、p53突变频率及生存率相关。LINE-1甲基化水平与ESCC中全基因组拷贝数改变的百分比呈显著负相关，反映了染色体的不稳定性。我们的研究结果表明，慢性炎症引起的全基因组低甲基化可能通过染色体不稳定启动食管鳞状细胞癌变。此外，染色体不稳定性与整体低甲基化可能与食管鳞癌的进展高度相关。
Background. Global DNA hypomethylation is associated with increased chromosomal instability and plays an important role in tumorigenesis. The methylation status of the long interspersed nuclear element-1 (LINE-1) element is a useful surrogate marker for global DNA methylation. Although LINE-1 hypomethylation is recognized as a poor prognostic marker, the correlation of LINE-1 methylation level with tumor suppressor gene mutation, chromosomal instability, and clinical significance in esophageal squamous cell carcinoma (ESCC) remains unclear.Methods. Using resected tumor tissues and the corresponding normal esophageal mucosa from 105 patients with ESCC, bisulfite pyrosequencing analysis was performed to quantify the LINE-1 methylation levels. p53 mutations in exons two to ten were detected by polymerase chain reaction direct sequencing. Chromosomal instability was assessed by single nucleotide polymorphism array comparative genomic hybridization analysis.Results. The LINE-1 methylation level of ESCC was significantly lower than matched normal mucosa. LINE-1 methylation levels of normal mucosa from the esophagus had a significant inverse correlation with both cigarette smoking and alcohol consumption of the study subjects. LINE-1 hypomethylation of ESCC was significantly associated with lymph node metastasis, lymphovascular invasion, the frequency of p53 mutation and poor survivability. The LINE-1 methylation levels in ESCC had a significant inverse association with the percentage of copy number alterations in the whole genome, mirroring chromosomal instability.Conclusions. Our results suggested that whole genome hypomethylation caused by chronic inflammation could initiate carcinogenesis of esophageal squamous cells through chromosomal instability. In addition, chromosomal instability associated with the global hypomethylation might correlate highly with the progression of ESCC.