结直肠癌中 RUNX3 启动子甲基化：与微卫星不稳定性的关系及其作为新型血清肿瘤标志物的适用性。
RUNX3 promoter methylation in colorectal cancer: its relationship with microsatellite instability and its suitability as a novel serum tumor marker.
机构信息
Department of Surgery, Division of Digestive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, 602-8566, Japan.
出版信息
Anticancer Res. 2010 Jul;30(7):2673-82.
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.
背景/目的：RUNX3 是一种新型胃癌肿瘤抑制因子。RUNX3 启动子的高甲基化与多种癌症有关，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 是一种与结直肠癌中微卫星不稳定性（MSI）相关的独特表型。在本研究中，我们研究了定量分析 RUNX3 启动子高甲基化作为新型血清肿瘤标志物的适用性。此外，我们还研究了结直肠癌中 RUNX3 启动子甲基化与 MSI 之间的关系。
患者和方法
我们开发的 RUNX3 实时定量甲基化特异性 PCR（RTQ-MSP）技术用于分析 119 例结直肠肿瘤和 344 例结直肠癌患者血清中 RUNX3 启动子的 CpG 位点。用 5 个微卫星标记物（BAT25、BAT26、D5S346、D2S123 和 D17S250）对 119 例结直肠肿瘤进行 MSI 分析。
结果
近端结肠肿瘤的 RUNX3 甲基化水平明显高于配对的正常组织（p=0.0438）。对临床病理参数的分析表明，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 甲基化水平显著升高相关。评估 RUNX3 甲基化与肿瘤 MSI 之间的关系显示，13 个高频 MSI（85%）的肿瘤中有 11 个呈 RUNX3 高甲基化，明显高于低频 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 甲基化水平明显与淋巴浸润（p=0.0487）和晚期病理分期（p=0.0466）相关。术后随访数据显示，复发病例的术前血清 RUNX3 甲基化水平明显高于非复发病例（p=0.0003）。同时分析术前血清癌胚抗原（CEA）水平显示，17.7%（61/344）为 CEA 阴性但 RUNX3 甲基化阳性，这意味着同时评估血清 RUNX3 甲基化和 CEA 应该可以提高结直肠癌的诊断。
结论
基于 RTQ-MSP 的血清 RUNX3 甲基化定量检测对结直肠癌的检测和监测很有用。
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