Date Published: April 1, 2019
Publisher: Public Library of Science
Author(s): Hiroki Harada, Kei Hosoda, Hiromitsu Moriya, Hiroaki Mieno, Akira Ema, Hideki Ushiku, Marie Washio, Nobuyuki Nishizawa, Satoru Ishii, Kazuko Yokota, Yoko Tanaka, Takeshi Kaida, Takafumi Soeno, Yoshimasa Kosaka, Masahiko Watanabe, Keishi Yamashita, Qian Tao.
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.
Quantitative 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.
(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. Promoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage.
Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide . Advanced gastric cancer, defined as depth of muscularis propria or beyond, still exhibited poor prognosis by curative surgery even in combination with effective adjuvant chemotherapy [2, 3], and require prognostic factors reflecting their biology to enrich high-risk patients for recurrences. Although several prognostic biomarkers have been reported by immunohistochemistry [4, 5] or by mRNA quantification [6, 7], they have weak points; the former included issues of intra-tumoral heterogeneity and cut-off line between positive and negative cases, while the latter is instable and not appropriate for routine examination. Hence, stable and quantitative methods have been anticipated to develop like DNA markers .
Promoter DNA of the CDO1 gene is frequently hypermethylated in human cancers including gastric cancer , which showed the highest AUC (0.95) to differentiate tumor tissues from the corresponding non-cancerous tissues . Hypermethylation in tumor tissues beyond 60% was designated as highly relevant methylation gene (HRMG), and CDO1 gene is the most common HRMG among human cancers . Using the best optimized cut-off value of TaqMeth V to discriminate tumor from non-cancerous tissues, CDO1 gene hypermethylation is found in 72~91% in various cancers [14, 18, 21, 28]. These frequencies were determined, based on comparison of tumor tissues to the corresponding non-cancerous tissues, and affected by the methylation level of non-cancerous tissues. For example, corresponding non-cancerous tissues were relatively highly methylated for CDO1 gene in gallbladder cancer, and threshold cut-off value became high and the frequencies were underestimated . Actual methylation frequencies are therefore considered higher than the report (~90% in almost human cancer). Anyway, CDO1 gene has an outstanding feature with regard to cancer-specific methylation in human cancer.