Genome-wide screening of DNA methylation associated with lymph node metastasis in esophageal squamous cell carcinoma
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Hiroaki Nagata1,6, Ken-Ichi Kozaki1,2,8, Tomoki Muramatsu1, Hidekazu Hiramoto1,6, Kousuke Tanimoto4, Naoto Fujiwara1,5, Seiya Imoto7, Daisuke Ichikawa6, Eigo Otsuji6, Satoru Miyano7, Tatsuyuki Kawano5 and Johji Inazawa1,2,3
1Department of Molecular Cytogenetics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
2Hard Tissue Genome Research Center, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
3Bioresource Research Center, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
4Genome Laboratory, Graduate School of Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
5Department of Esophageal and General Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
6Department of Digestive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
7Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
8Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
Johji Inazawa, email: [email protected]
Keywords: esophageal squamous cell carcinoma, DNA methylation, predictive biomarker, lymph node metastasis, pyrosequencing analysis
Received: June 16, 2016 Accepted: March 28, 2017 Published: April 17, 2017
Lymph node metastasis (LNM) of esophageal squamous cell carcinoma (ESCC) is well-known to be an early event associated with poor prognosis in patients with ESCC. Recently, tumor-specific aberrant DNA methylation of CpG islands around the promoter regions of tumor-related genes has been investigated as a possible biomarker for use in early diagnosis and prediction of prognosis. However, there are few DNA methylation markers able to predict the presence of LNM in ESCC. To identify DNA methylation markers associated with LNM of ESCC, we performed a genome-wide screening of DNA methylation status in a discovery cohort of 67 primary ESCC tissues and their paired normal esophageal tissues using the Illumina Infinium HumanMethylation450 BeadChip. In this screening, we focused on differentially methylated regions (DMRs) that were associated with LNM of ESCC, as prime candidates for DNA methylation markers. We extracted three genes, HOXB2, SLC15A3, and SEPT9, as candidates predicting LNM of ESCC, using pyrosequencing and several statistical analyses in the discovery cohort. We confirmed that HOXB2 and SEPT9 were highly methylated in LNM-positive tumors in 59 ESCC validation samples. These results suggested that HOXB2 and SEPT9 may be useful epigenetic biomarkers for the prediction of the presence of LNM in ESCC.
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