Department of Surgery, Kitasato University Hospital, Kitasato, Minami-ku, Sagamihara, Kanagawa, Japan.
Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kitasato, Minami-ku, Sagamihara, Kanagawa, Japan.
PLoS One. 2018 Oct 16;13(10):e0205864. doi: 10.1371/journal.pone.0205864. eCollection 2018.
Promoter DNA methylation of Cysteine dioxygenase type1 (CDO1) gene has been clarified as a molecular diagnostic and prognostic indicator in various human cancers. The aim of this study is to investigate the clinical relevance of CDO1 methylation in primary biliary tract cancer (BTC).
CDO1 DNA methylation was assessed by quantitative methylation-specific PCR in 108 BTC tumor tissues and 101 corresponding normal tissues. BTC was composed of extrahepatic cholangiocarcinoma (EHCC) (n = 81) and ampullary carcinoma (AC) (n = 27).
The CDO1 methylation value in the tumor tissues was significantly higher than that in the corresponding normal tissues (p<0.0001). The overall survival (OS) in EHCC patients with hypermethylation was poorer than those with hypomethylation (p = 0.0018), whereas there was no significant difference in AC patients. Multivariate analysis identified that CDO1 hypermethylation, preoperative serum CA19-9 and perineural invasion were independent prognostic factors in EHCC. The EHCC patients with CDO1 hypermethylation exhibited more dismal prognosis than those with hypomethylation even in low group of CA19-9 level (p = 0.0006).
Our study provided evidence that promoter DNA methylation of CDO1 gene could be an excellent molecular diagnostic and prognostic biomarker in primary EHCC. The combination of CDO1 methylation and preoperative serum CA19-9 effectively enriched EHCC patients who showed the most dismal prognosis. These markers would be beneficial for clinical clarification of the optimal strategies in EHCC.
半胱氨酸双加氧酶 1（CDO1）基因启动子 DNA 甲基化已被证实是多种人类癌症的分子诊断和预后指标。本研究旨在探讨原发性胆管癌（BTC）中 CDO1 甲基化的临床相关性。
通过定量甲基化特异性 PCR 检测 108 例 BTC 肿瘤组织和 101 例相应正常组织中的 CDO1 DNA 甲基化。BTC 由肝外胆管癌（EHCC）（n = 81）和壶腹癌（AC）（n = 27）组成。
肿瘤组织中的 CDO1 甲基化值明显高于相应的正常组织（p<0.0001）。EHCC 患者中 CDO1 高甲基化的总体生存率（OS）比低甲基化患者差（p = 0.0018），而 AC 患者则无显著差异。多因素分析表明，CDO1 高甲基化、术前血清 CA19-9 和神经周围侵犯是 EHCC 的独立预后因素。即使在 CA19-9 水平较低的组中，CDO1 高甲基化的 EHCC 患者的预后也比低甲基化患者更差（p = 0.0006）。
本研究提供的证据表明，CDO1 基因启动子 DNA 甲基化可能是原发性 EHCC 的一种优秀的分子诊断和预后生物标志物。CDO1 甲基化与术前血清 CA19-9 的结合可有效富集预后最差的 EHCC 患者。这些标志物将有助于阐明 EHCC 的最佳治疗策略。
