Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma
Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma
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DOI：
10.1093/jnci/92.22.1805
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发表时间：
2000-11-15
期刊：
影响因子：
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通讯作者：
Meltzer, SJ
中科院分区：
文献类型：
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作者：
Kawakami, K;Brabender, J;Meltzer, SJ
背景：染色体5 q21 -22上的大肠腺瘤性息肉病（APC）基因座在食管癌中存在频繁的杂合性丢失（洛）。然而，APC基因截短突变在食管癌中的发生率很低。由于已知启动子区的高甲基化会影响其他几种肿瘤抑制基因，我们研究了APC启动子区是否在食管癌患者中高甲基化，以及这种异常是否可以作为预后的血浆生物标志物。方法：我们检测了来自肿瘤组织的DNA和来自食管癌患者的APC基因启动子区的高甲基化。我们使用最大卡方统计量来确定血浆中高甲基化APC DNA水平的判别性截止值，并使用Bootstrap样模拟来确定P值以测试这种关联的强度。该截止值用于生成Kaplan-Meier生存曲线。所有P值均基于双侧检验。结果如下：APC基因启动子区的甲基化发生在异常食管组织中的48（92%）52例食管腺癌，16（50%）32例食管鳞状细胞癌，17（39.5%）43例Barrett的化生，而不是在匹配的正常食管组织。在52例腺癌患者中的13例（25%）和32例鳞癌患者中的2例（6.3%）血浆中观察到APC DNA高甲基化。高水平的血浆甲基化APC DNA与患者生存率降低有统计学意义（P = 0.016），结论：APC启动子区在大多数原发性食管腺癌患者的肿瘤中高甲基化。血浆中高甲基化APC基因DNA水平可能是食管腺癌患者生物侵袭性疾病的有用生物标志物，应作为其他肿瘤类型的潜在生物标志物进行评估。
Background: The adenomatous polyposis coli (APC) locus on chromosome 5q21-22 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. However, the prevalence of truncating mutations in the APC gene in esophageal carcinomas is low. Because hypermethylation of promoter regions is known to affect several other tumor suppressor genes, we investigated whether the APC promoter region is hypermethylated in esophageal cancer patients and whether this abnormality could serve as a prognostic plasma biomarker, Methods: We assayed DNA from tumor tissue and matched plasma from esophageal cancer patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff value for hypermethylated APC DNA levels in plasma and used bootstrap-like simulations to determine the P value to test for the strength of this association. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests. Results: Hypermethylation of the promoter region of the APC gene occurred in abnormal esophageal tissue in 48 (92%) of 52 patients with esophageal adenocarcinoma, in 16 (50%) of 32 patients with esophageal squamous cell carcinoma, and in 17 (39.5%) of 43 patients with Barrett's metaplasia but not in matching normal esophageal tissues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival (P = .016), Conclusion: The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types.