Abstract
BackgroundThere have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a cancer-specific aberration, in human gastric cancer.MethodsQuantitative CDO1 methylation value (TaqMeth V) was initially calculated in 138 gastric cancer patients operated in 2005, and its clinical significance was elucidated. As a subsequent expanded set, 154 gastric cancer patients with pathological stage (pStage) II / III with no postoperative therapy were validated between 2000 and 2010.Results(1) Median TaqMeth V of CDO1 gene methylation of gastric cancer was 25.6, ranging from 0 to 120.9. As pStage progressed, CDO1 TaqMeth V became higher (p < 0.0001). (2) The optimal cut-off value was determined to be 32.6; gastric cancer patients with high CDO1 gene methylation showed a significantly worse prognosis than those with low CDO1 gene methylation (p < 0.0001). (3) A multivariate cox proportional hazards model identified high CDO1 gene methylation (p = 0.033) as an independent prognostic factor. (4) The results were recapitulated in the expanded set in pStage III, where high CDO1 gene methylation group had a significantly worse prognosis than low CDO1 gene methylation group (p = 0.0065). Hematogenous metastasis was unique in pStage III with high CDO1 gene methylation (p = 0.0075). (5) Anchorage independent growth was reduced in several gastric cancer cell lines due to forced expression of the CDO1 gene, suggesting that abnormal CDO1 gene expression may represent distant metastatic ability.ConclusionsPromoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage.
Highlights
Gastric cancer is the fifth most common malignancy and the third leading cause of cancerrelated death worldwide [1]
Promoter DNA hypermethylation of Cysteine dioxygenase type 1 (CDO1) gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage
Epigenetic gene silencing of the tumor suppresser genes (TSGs) through promoter DNA hypermethylation is a unique feature in human cancers, whereas such cancer specific methylation is rather a rare event [8, 9]
Summary
Gastric cancer is the fifth most common malignancy and the third leading cause of cancerrelated death worldwide [1]. Epigenetic gene silencing of the tumor suppresser genes (TSGs) through promoter DNA hypermethylation is a unique feature in human cancers, whereas such cancer specific methylation is rather a rare event [8, 9]. We had developed pharmacologic reversal of epigenetic silencing and uncovered a myriad of transcriptionally repressed genes in human cancers [10,11,12,13], and have identified outstanding candidate TSG with frequent promoter DNA methylation, a cysteine dioxygenase type 1 (CDO1) gene in human cancers including gastric cancer [14]. There have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a cancer-specific aberration, in human gastric cancer
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