Genome-wide Hypomethylation and Specific Tumor-Related Gene Hypermethylation are Associated with Esophageal Squamous Cell Carcinoma Outcome

Sojun Hoshimoto, Hiroya Takeuchi, Shigeshi Ono, Myung Shin Sim, Jamie L. Huynh, Sharon K. Huang, Diego M. Marzese, Yuukou Kitagawa, Dave S.B. Hoon

Research output: Contribution to journalArticle

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Abstract

INTRODUCTION:: Esophageal squamous cell carcinoma (ESCC) is a cancer of variable outcomes with limited effective treatments resulting in poor overall survival (OS). Epigenetic alterations contributing to this deadly cancer type that can be used as novel therapeutic or diagnostic targets are still poorly understood.

METHODS:: We explored genome-wide DNA methylation data from The Cancer Genome Atlas (TCGA) project and identified a panel of tumor-related genes (TRGs) hypermethylated in ESCC. The methylation statuses of RASSF1, RARB, CDKN2A (p16INK4a, p14ARF), APC, and RUNX3 genes and long interspersed nucleotide element-1 (LINE-1) were validated in a large cohort (n=140) of clinically well-annotated ESCC specimens and esophageal normal mucosa (n=28) using a quantitative methylation-specific PCR.

RESULTS:: Hypermethylation of RARB, p16INK4a, RASSF1, APC, RUNX3, and p14ARF were observed in 55%, 24%, 20%, 19%, 14%, and 8% of specimens, respectively. Hypermethylation of APC was significantly associated with tumor depth (p=0.02) and AJCC stage (P=0.03). Global DNA methylation level, assessed by LINE-1, was significantly lower in ESCC than in normal mucosa (P<0.0001), and lower in ≥T2 (n=69) than T1 tumors (n=45) (P=0.03). There was a significant inverse correlation between LINE-1 and RARB methylation (p=0.008). Importantly, hypermethylation of RASSF1 and APC genes was significantly associated with overall survival (OS; P=0.006 and P=0.007, respectively). In addition, patients with tumors containing a higher number of methylated genes (>2 genes) presented worse OS (P=0.003).

CONCLUSIONS:: This study demonstrates that epigenetic alterations of a panel of TRGs and the non-coding region LINE-1 can be used as prognostic indicators and help in clinical management of ESCC patients.

Original languageEnglish
JournalJournal of Thoracic Oncology
DOIs
Publication statusAccepted/In press - 2014 Dec 15

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Long Interspersed Nucleotide Elements
Genome
Tumor Suppressor Protein p14ARF
Genes
Neoplasms
DNA Methylation
Epigenomics
Methylation
APC Genes
Survival
Atlases
Esophageal Squamous Cell Carcinoma
Mucous Membrane
Polymerase Chain Reaction
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Genome-wide Hypomethylation and Specific Tumor-Related Gene Hypermethylation are Associated with Esophageal Squamous Cell Carcinoma Outcome. / Hoshimoto, Sojun; Takeuchi, Hiroya; Ono, Shigeshi; Sim, Myung Shin; Huynh, Jamie L.; Huang, Sharon K.; Marzese, Diego M.; Kitagawa, Yuukou; Hoon, Dave S.B.

In: Journal of Thoracic Oncology, 15.12.2014.

Research output: Contribution to journalArticle

Hoshimoto, Sojun ; Takeuchi, Hiroya ; Ono, Shigeshi ; Sim, Myung Shin ; Huynh, Jamie L. ; Huang, Sharon K. ; Marzese, Diego M. ; Kitagawa, Yuukou ; Hoon, Dave S.B. / Genome-wide Hypomethylation and Specific Tumor-Related Gene Hypermethylation are Associated with Esophageal Squamous Cell Carcinoma Outcome. In: Journal of Thoracic Oncology. 2014.
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abstract = "INTRODUCTION:: Esophageal squamous cell carcinoma (ESCC) is a cancer of variable outcomes with limited effective treatments resulting in poor overall survival (OS). Epigenetic alterations contributing to this deadly cancer type that can be used as novel therapeutic or diagnostic targets are still poorly understood.METHODS:: We explored genome-wide DNA methylation data from The Cancer Genome Atlas (TCGA) project and identified a panel of tumor-related genes (TRGs) hypermethylated in ESCC. The methylation statuses of RASSF1, RARB, CDKN2A (p16INK4a, p14ARF), APC, and RUNX3 genes and long interspersed nucleotide element-1 (LINE-1) were validated in a large cohort (n=140) of clinically well-annotated ESCC specimens and esophageal normal mucosa (n=28) using a quantitative methylation-specific PCR.RESULTS:: Hypermethylation of RARB, p16INK4a, RASSF1, APC, RUNX3, and p14ARF were observed in 55{\%}, 24{\%}, 20{\%}, 19{\%}, 14{\%}, and 8{\%} of specimens, respectively. Hypermethylation of APC was significantly associated with tumor depth (p=0.02) and AJCC stage (P=0.03). Global DNA methylation level, assessed by LINE-1, was significantly lower in ESCC than in normal mucosa (P<0.0001), and lower in ≥T2 (n=69) than T1 tumors (n=45) (P=0.03). There was a significant inverse correlation between LINE-1 and RARB methylation (p=0.008). Importantly, hypermethylation of RASSF1 and APC genes was significantly associated with overall survival (OS; P=0.006 and P=0.007, respectively). In addition, patients with tumors containing a higher number of methylated genes (>2 genes) presented worse OS (P=0.003).CONCLUSIONS:: This study demonstrates that epigenetic alterations of a panel of TRGs and the non-coding region LINE-1 can be used as prognostic indicators and help in clinical management of ESCC patients.",
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T1 - Genome-wide Hypomethylation and Specific Tumor-Related Gene Hypermethylation are Associated with Esophageal Squamous Cell Carcinoma Outcome

AU - Hoshimoto, Sojun

AU - Takeuchi, Hiroya

AU - Ono, Shigeshi

AU - Sim, Myung Shin

AU - Huynh, Jamie L.

AU - Huang, Sharon K.

AU - Marzese, Diego M.

AU - Kitagawa, Yuukou

AU - Hoon, Dave S.B.

PY - 2014/12/15

Y1 - 2014/12/15

N2 - INTRODUCTION:: Esophageal squamous cell carcinoma (ESCC) is a cancer of variable outcomes with limited effective treatments resulting in poor overall survival (OS). Epigenetic alterations contributing to this deadly cancer type that can be used as novel therapeutic or diagnostic targets are still poorly understood.METHODS:: We explored genome-wide DNA methylation data from The Cancer Genome Atlas (TCGA) project and identified a panel of tumor-related genes (TRGs) hypermethylated in ESCC. The methylation statuses of RASSF1, RARB, CDKN2A (p16INK4a, p14ARF), APC, and RUNX3 genes and long interspersed nucleotide element-1 (LINE-1) were validated in a large cohort (n=140) of clinically well-annotated ESCC specimens and esophageal normal mucosa (n=28) using a quantitative methylation-specific PCR.RESULTS:: Hypermethylation of RARB, p16INK4a, RASSF1, APC, RUNX3, and p14ARF were observed in 55%, 24%, 20%, 19%, 14%, and 8% of specimens, respectively. Hypermethylation of APC was significantly associated with tumor depth (p=0.02) and AJCC stage (P=0.03). Global DNA methylation level, assessed by LINE-1, was significantly lower in ESCC than in normal mucosa (P<0.0001), and lower in ≥T2 (n=69) than T1 tumors (n=45) (P=0.03). There was a significant inverse correlation between LINE-1 and RARB methylation (p=0.008). Importantly, hypermethylation of RASSF1 and APC genes was significantly associated with overall survival (OS; P=0.006 and P=0.007, respectively). In addition, patients with tumors containing a higher number of methylated genes (>2 genes) presented worse OS (P=0.003).CONCLUSIONS:: This study demonstrates that epigenetic alterations of a panel of TRGs and the non-coding region LINE-1 can be used as prognostic indicators and help in clinical management of ESCC patients.

AB - INTRODUCTION:: Esophageal squamous cell carcinoma (ESCC) is a cancer of variable outcomes with limited effective treatments resulting in poor overall survival (OS). Epigenetic alterations contributing to this deadly cancer type that can be used as novel therapeutic or diagnostic targets are still poorly understood.METHODS:: We explored genome-wide DNA methylation data from The Cancer Genome Atlas (TCGA) project and identified a panel of tumor-related genes (TRGs) hypermethylated in ESCC. The methylation statuses of RASSF1, RARB, CDKN2A (p16INK4a, p14ARF), APC, and RUNX3 genes and long interspersed nucleotide element-1 (LINE-1) were validated in a large cohort (n=140) of clinically well-annotated ESCC specimens and esophageal normal mucosa (n=28) using a quantitative methylation-specific PCR.RESULTS:: Hypermethylation of RARB, p16INK4a, RASSF1, APC, RUNX3, and p14ARF were observed in 55%, 24%, 20%, 19%, 14%, and 8% of specimens, respectively. Hypermethylation of APC was significantly associated with tumor depth (p=0.02) and AJCC stage (P=0.03). Global DNA methylation level, assessed by LINE-1, was significantly lower in ESCC than in normal mucosa (P<0.0001), and lower in ≥T2 (n=69) than T1 tumors (n=45) (P=0.03). There was a significant inverse correlation between LINE-1 and RARB methylation (p=0.008). Importantly, hypermethylation of RASSF1 and APC genes was significantly associated with overall survival (OS; P=0.006 and P=0.007, respectively). In addition, patients with tumors containing a higher number of methylated genes (>2 genes) presented worse OS (P=0.003).CONCLUSIONS:: This study demonstrates that epigenetic alterations of a panel of TRGs and the non-coding region LINE-1 can be used as prognostic indicators and help in clinical management of ESCC patients.

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