Kawakami K, Brabender J, Lord R V, Groshen S, Greenwald B D, Krasna M J, Yin J, Fleisher A S, Abraham J M, Beer D G, Sidransky D, Huss H T, Demeester T R, Eads C, Laird P W, Ilson D H, Kelsen D P, Harpole D, Moore M B, Danenberg K D, Danenberg P V, Meltzer S J
Department of Biochemistry and Molecular Biology and Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
J Natl Cancer Inst. 2000 Nov 15;92(22):1805-11. doi: 10.1093/jnci/92.22.1805.
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.
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.
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).
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.
5号染色体q21 - 22区域的腺瘤性结肠息肉病（APC）基因座在食管癌中常出现杂合性缺失（LOH）。然而，食管癌中APC基因截短突变的发生率较低。由于已知启动子区域的高甲基化会影响其他几个肿瘤抑制基因，我们研究了食管癌患者中APC启动子区域是否发生高甲基化，以及这种异常是否可作为一种预后血浆生物标志物。
我们检测了食管癌患者肿瘤组织及配对血浆中APC基因启动子区域的高甲基化情况。我们使用最大卡方统计量来确定血浆中高甲基化APC DNA水平的鉴别临界值，并使用类似自助法的模拟来确定检验这种关联强度的P值。该临界值用于生成Kaplan - Meier生存曲线。所有P值均基于双侧检验。
52例食管腺癌患者中有48例（92%）、32例食管鳞状细胞癌患者中有16例（50%）以及43例巴雷特化生患者中有17例（39.5%）的异常食管组织中出现了APC基因启动子区域的高甲基化，但在配对的正常食管组织中未出现。52例腺癌患者中有13例（25%）、32例鳞状细胞癌患者中有2例（6.3%）的血浆中观察到高甲基化的APC DNA。血浆中高甲基化APC DNA水平与患者生存率降低在统计学上具有显著相关性（P = 0.016）。
大多数原发性食管腺癌患者的肿瘤中APC启动子区域发生了高甲基化。血浆中高甲基化APC基因DNA水平可能是食管腺癌患者生物学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。
