RUNX3 promoter methylation in colorectal cancer: its relationship with microsatellite instability and its suitability as a novel serum tumor marker.
RUNX3 promoter methylation in colorectal cancer: its relationship with microsatellite instability and its suitability as a novel serum tumor marker.
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发表时间：
2010-07
影响因子：
2
通讯作者：
M. Nishio;C. Sakakura;T. Nagata;S. Komiyama;A. Miyashita;Takuo Hamada;Yoshiaki Kuryu;H. Ikoma
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作者：
M. Nishio;C. Sakakura;T. Nagata;S. Komiyama;A. Miyashita;Takuo Hamada;Yoshiaki Kuryu;H. Ikoma
背景/目的RUNX3是一种新型的胃癌肿瘤抑制因子。RUNX3启动子超甲基化与许多类型的癌症有关，包括结直肠癌。此外，RUNX3启动子是CpG岛甲基化表型（CIMP）特异性启动子之一。CIMP是结直肠癌中与微卫星不稳定性（MSI）相关的一种独特表型。本研究探讨了RUNX3启动子超甲基化定量分析作为一种新型血清肿瘤标志物的适用性。此外，我们还研究了RUNX3启动子甲基化与结直肠癌MSI之间的关系。采用我们开发的RUNX3实时定量甲基化特异性PCR （RTQ-MSP）技术，分析了119例结直肠癌肿瘤和344例结直肠癌患者血清中RUNX3启动子中的CpG位点。采用5种微卫星标记物（BAT25、BAT26、D5S346、D2S123和D17S250）对119例结直肠肿瘤进行MSI分析。结果结肠近端肿瘤的RUNX3甲基化水平明显高于配对的正常组织（p=0.0438）。临床病理参数分析显示，近端位置（p=0.0054）、淋巴浸润（p<0.0001）和晚期病理分期（p=0.0018）与RUNX3甲基化显著升高相关。评估RUNX3甲基化与肿瘤MSI之间的关系显示，13例高频MSI肿瘤中有11例（85%）RUNX3超甲基化阳性，显著高于低频MSI或微卫星稳定的肿瘤（34%,p=0.0070）。在344例结直肠癌患者的术前血清中，RUNX3甲基化水平显著升高与淋巴浸润（p=0.0487）和病理分期进展（p=0.0466）相关。术后随访数据显示，复发患者术前血清RUNX3甲基化水平明显高于未复发患者（p=0.0003）。同时分析术前血清癌胚抗原（CEA）水平，17.7%（61/344）患者CEA阴性，而RUNX3甲基化阳性，提示同时评估血清RUNX3甲基化和CEA可提高结直肠癌的诊断。结论基于rtq - msp的血清RUNX3甲基化定量检测可用于大肠癌的检测和监测。
BACKGROUND/AIM RUNX3 is a novel gastric cancer tumor suppressor. RUNX3 promoter hypermethylation is associated with many types of cancer, including colorectal cancer. Furthermore, the RUNX3 promotor is one of the CpG island methylator phenotype (CIMP)-specific promotors. CIMP is a distinct phenotype associated with microsatellite instability (MSI) in colorectal cancer. In this study, the suitability of the quantitative analysis of RUNX3 promoter hypermethylation as a novel serum tumor marker was investigated. Moreover, we investigated the relationship between RUNX3 promoter methylation and MSI in colorectal cancer. PATIENTS AND METHODS A RUNX3 real-time quantitative methylation-specific PCR (RTQ-MSP) technique we developed was used to analyze the CpG sites in the RUNX3 promoter of 119 colorectal tumors and 344 sera from colorectal cancer patients. MSI analysis of 119 colorectal tumors was performed with five microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250). RESULTS Proximal colon tumors exhibited significantly higher RUNX3 methylation than their paired normal tissues (p=0.0438). Analysis of the clinicopathological parameters revealed that a proximal location (p=0.0054), lymphatic invasion (p<0.0001), and an advanced pathological stage (p=0.0018) were associated with significantly higher RUNX3 methylation. Assessment of the relationship between RUNX3 methylation and tumor MSI revealed 11 out of 13 tumors with high-frequency MSI (85%) were positive for RUNX3 hypermethylation, significantly more than the tumors with low-frequency MSI or which were microsatellite stable (34%, p=0.0070). In preoperative sera from 344 colorectal cancer patients, significantly higher RUNX3 methylation was associated with lymphatic invasion (p=0.0487) and an advanced pathological stage (p=0.0466). Post-operative follow-up data revealed that recurrence cases exhibited significantly higher preoperative serum RUNX3 methylation than non-recurrence cases (p=0.0003). Concomitant analysis of carcinoembryonic antigen (CEA) levels in the preoperative sera showed that 17.7% (61/344) were CEA-negative but RUNX3 methylation-positive, which means assessing both serum RUNX3 methylation and CEA should improve diagnosis of colorectal carcinoma. CONCLUSION RTQ-MSP-based quantification of serum RUNX3 methylation is useful for the detection and monitoring of colorectal cancer.