Prognostic significance of promoter DNA hypermethylation of the cysteine dioxygenase 1 (CDO1) gene in primary gallbladder cancer and gallbladder disease.

Kazuharu Igarashi,Nobuyuki Nishizawa,Yusuke Kumamoto,Hiroshi Kawamata,Hiroshi Katoh,Keishi Yamashita,Ryo Nishiyama,Keita Kojima,Yosuke Ooizumi,Masahiko Watanabe,Hiroshi Tajima,Takashi Kaizu,Aamir Ahmad

doi:10.1371/journal.pone.0188178

Kazuharu Igarashi, Nobuyuki Nishizawa + Show 11 more

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https://doi.org/10.1371/journal.pone.0188178

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Journal: PloS one	Publication Date: Nov 21, 2017
Citations: 18	License type: CC BY 4.0

Affiliation: Kitasato University Hospital

Abstract

BackgroundAberrant promoter DNA methylation of the cysteine dioxygenase 1 (CDO1) gene is found in various human cancers and is associated with clinical outcome. In this study, we assessed for the first time the clinicopathological significance of CDO1 methylation in primary gallbladder cancer (GBC) in comparison with non-malignant gallbladder disease.MethodsCDO1 DNA methylation was quantified using quantitative TaqMan methylation specific PCR (Q-MSP) in 99 primary GBC patients together with the 78 corresponding non-tumor tissues and 26 benign gallbladder disease (including 7 patients with xanthogranulomatous cholecystitis) who underwent surgical resection between 1986 and 2014.ResultsThe average CDO1 TaqMeth value of primary GBCs was 23.5±26. These values were significantly higher than those of corresponding non-tumor tissues (average 8±13, p < .0001) and diseased gallbladder tissues from patients with benign gallbladder diseases (average 0.98±1.6, p < .0001). CDO1 hypermethylation is also found in xanthogranulomatous cholecystitis. Using a cut-off value of 17.7, GBC cases with CDO1 hypermethylation (n = 47) showed significantly poorer prognosis than those with CDO1 hypomethylation (n = 52) (p = 0.0023). Multivariate Cox proportional hazards analysis identified that CDO1 hypermethylation was an independent prognostic factor. Notably, CDO1 hypermethylation showed prognostic relevance, especially in stage II GBC, in which it is highly anticipated to work as a predictive marker for candidates of adjuvant therapy.ConclusionsPromoter NA methylation of CDO1 was demonstrated for the first time to be a cancer-associated methylation in primary GBC, and it has the potential to be a prognostic biomarker of GBC for high-risk patients with stage II GBC.

Highlights

Cancer statistics predicted an estimated 11,420 new gallbladder cancer (GBC) cases and 3,710 GBC deaths in the United States in 2016 [1]
Promoter NA methylation of cysteine dioxygenase 1 (CDO1) was demonstrated for the first time to be a cancer-associated methylation in primary GBC, and it has the potential to be a prognostic biomarker of GBC for high-risk patients with stage II GBC
In the 2 GBC cell lines, no basal expression of CDO1 was seen (Fig 1A), and silenced expression of CDO1 gene was robustly reactivated after treatment with the demethylating agent, 5-Aza-dC, 5-Aza-dC and trichostatin A (TSA) (Fig 1B)

Summary

Introduction

Cancer statistics predicted an estimated 11,420 new gallbladder cancer (GBC) cases and 3,710 GBC deaths in the United States in 2016 [1]. GBC has been associated with a poor prognosis, and the depth of tumor invasion and the presence of lymph node metastasis have been reported to be important prognostic factors [2]. High rates of both local and distant recurrence have prompted interest in the use of adjuvant chemotherapy and radiation therapy (RT). We and others investigated strong association of CDO1 gene promoter DNA methylation with poor prognosis in primary breast cancer [9], renal clear-cell cancer [10], esophageal squamous cell carcinoma [11] and Barrett esophagus adenocarcinoma [12]. We assessed for the first time the clinicopathological significance of CDO1 methylation in primary gallbladder cancer (GBC) in comparison with non-malignant gallbladder disease

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