Watanabe Yoshiyuki, Kim Hyun Soo, Castoro Ryan J, Chung Woonbok, Estecio Marcos R H, Kondo Kimie, Guo Yi, Ahmed Saira S, Toyota Minoru, Itoh Fumio, Suk Ki Tae, Cho Mee-Yon, Shen Lanlan, Jelinek Jaroslav, Issa Jean-Pierre J
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Gastroenterology. 2009 Jun;136(7):2149-58. doi: 10.1053/j.gastro.2009.02.085. Epub 2009 Apr 16.
BACKGROUND & AIMS: Aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for detection of gastric neoplasia. We hypothesized that methylation analysis of DNA recovered from gastric washes could be used to detect gastric cancer.
We studied 51 candidate genes in 7 gastric cancer cell lines and 24 samples (training set) and identified 6 for further studies. We examined the methylation status of these genes in a test set consisting of 131 gastric neoplasias at various stages. Finally, we validated the 6 candidate genes in a different population of 40 primary gastric cancer samples and 113 nonneoplastic gastric mucosa samples.
Six genes (MINT25, RORA, GDNF, ADAM23, PRDM5, MLF1) showed frequent differential methylation between gastric cancer and normal mucosa in the training, test, and validation sets. GDNF and MINT25 were most sensitive molecular markers of early stage gastric cancer, whereas PRDM5 and MLF1 were markers of a field defect. There was a close correlation (r = 0.5-0.9, P = .03-.001) between methylation levels in tumor biopsy and gastric washes. MINT25 methylation had the best sensitivity (90%), specificity (96%), and area under the receiver operating characteristic curve (0.961) in terms of tumor detection in gastric washes.
These findings suggest MINT25 is a sensitive and specific marker for screening in gastric cancer. Additionally, we have developed a new method for gastric cancer detection by DNA methylation in gastric washes.
异常DNA甲基化是胃癌发生过程中早期且常见的现象，可能有助于胃癌的检测。我们推测，对胃冲洗液中回收的DNA进行甲基化分析可用于检测胃癌。
我们研究了7种胃癌细胞系和24个样本（训练集）中的51个候选基因，并确定了6个用于进一步研究。我们在由131个不同阶段的胃肿瘤组成的测试集中检测了这些基因的甲基化状态。最后，我们在由40个原发性胃癌样本和113个非肿瘤性胃黏膜样本组成的不同人群中验证了这6个候选基因。
在训练集、测试集和验证集中，6个基因（MINT25、RORA、GDNF、ADAM23、PRDM5、MLF1）在胃癌和正常黏膜之间表现出频繁的差异甲基化。GDNF和MINT25是早期胃癌最敏感的分子标志物，而PRDM5和MLF1是癌前病变的标志物。肿瘤活检和胃冲洗液中的甲基化水平之间存在密切相关性（r = 0.5 - 0.9，P = 0.03 - 0.001）。就胃冲洗液中的肿瘤检测而言，MINT25甲基化具有最佳的敏感性（90%）、特异性（96%）和受试者工作特征曲线下面积（0.961）。
这些发现表明MINT25是胃癌筛查的敏感且特异的标志物。此外，我们开发了一种通过胃冲洗液中DNA甲基化检测胃癌的新方法。
