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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 4/2014

01-12-2014 | Translational Research and Biomarkers

Chromosomal Instability Associated with Global DNA Hypomethylation is Associated with the Initiation and Progression of Esophageal Squamous Cell Carcinoma

Authors: Hiroyuki Kawano, MD, Hiroshi Saeki, MD, PhD, Hiroyuki Kitao, PhD, Yasuo Tsuda, MD, Hajime Otsu, MD, Koji Ando, MD, PhD, Shuhei Ito, MD, PhD, Akinori Egashira, MD, PhD, Eiji Oki, MD, PhD, Masaru Morita, MD, PhD, Yoshinao Oda, MD, PhD, Yoshihiko Maehara, MD, PhD

Published in: Annals of Surgical Oncology | Special Issue 4/2014

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Abstract

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.
Appendix
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Metadata
Title
Chromosomal Instability Associated with Global DNA Hypomethylation is Associated with the Initiation and Progression of Esophageal Squamous Cell Carcinoma
Authors
Hiroyuki Kawano, MD
Hiroshi Saeki, MD, PhD
Hiroyuki Kitao, PhD
Yasuo Tsuda, MD
Hajime Otsu, MD
Koji Ando, MD, PhD
Shuhei Ito, MD, PhD
Akinori Egashira, MD, PhD
Eiji Oki, MD, PhD
Masaru Morita, MD, PhD
Yoshinao Oda, MD, PhD
Yoshihiko Maehara, MD, PhD
Publication date
01-12-2014
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue Special Issue 4/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-3818-z

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