Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer
Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer
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DOI：
10.1158/1078-0432.ccr-07-4522
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发表时间：
2008-10-01
影响因子：
11.5
通讯作者：
Corvalan, Alejandro H.
中科院分区：
文献类型：
--
作者：
Bernal, Carolina;Aguayo, Francisco;Corvalan, Alejandro H.
目的：胃癌早期诊断是可以治愈的。然而，由于缺乏筛查程序，大多数病例在晚期才被诊断出来。因此，鉴定血浆生物标志物进行早期检测是必要的。实验设计：为了寻找这些生物标志物，我们回顾性收集32例胃癌患者（试验组）的原发组织，采用甲基化特异性PCR方法评估了24个基因的DNA甲基化模式。在5-aza-2'-脱氧胞苷处理后的MKN-45细胞系中，评估了甲基化与基因表达的相关性。接下来，在43例前瞻性收集的胃癌病例的原发组织和血浆样本以及31例无症状年龄和性别匹配的对照组（验证组）的血浆样本中评估最常见的高甲基化基因。结果：在实验组中，至少50%的病例中有11个基因（APC、SHP1、E-cadherin、ER、primo、SEMA3B、3OST2、p14、p15、DAPK和p16）发生了高甲基化。8个基因（BRCA1、p73、RAR β、hMLH1、RIZI、RUNX3、MGMT、TIMP3）与一种特殊的胃癌变异印环细胞型有统计学意义（P = 0.03）。验证组的7个基因（APC、SHP1、E-cadherin、ER、primo、SEMA3B和3OST2）随后被评估。我们证实了所有七个基因在原发肿瘤中甲基化的高频率。然而，在对血浆样本中，只有APC和Reprimo经常发生甲基化。在无症状对照中，与胃癌患者的血浆相比，只有Reprimo很少发生甲基化（P < 0.001）。结论：我们的研究结果确定了与印戒细胞型组织学和异常高甲基化相关的特异性甲基化谱，作为胃癌早期检测的潜在生物标志物。
Purpose: Gastric cancer is a curable disease if diagnosed at early stage. However, most cases are diagnosed at advanced stage because of the lack of screening programs. Therefore, the identification of plasma biomarkers for early detection is necessary.Experimental Design: To search for these biomarkers, we evaluated the DNA methylation patterns of 24 genes by Methylation-specific PCR in primary tissues from 32 retrospectively collected gastric cancer cases (testing group). Correlation between methylation and gene expression was evaluated in the MKN-45 cell line after treatment with 5-aza-2'-deoxycytidine. The most frequently hypermethylated genes were next evaluated in primary tissues and plasma samples from 43 prospectively collected gastric cancer cases as well as plasma samples from 31 asymptomatic age- and gender-matched controls (validation group).Results: In the testing group, 11 genes were hypermethylated in at least 50% of cases (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, 3OST2, p14, p15, DAPK, and p16). Eight genes (BRCA1, p73, RAR beta, hMLH1, RIZI, RUNX3, MGMT, and TIMP3) were statistically associated with a particular variant of gastric cancer, the signet-ring cell type (P = 0.03). Seven genes (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, and 3OST2) were next evaluated in the validation group. We confirm the high frequency of methylation in primary tumors for all seven genes. However, only APC and Reprimo were frequently methylated in pair plasma samples. In asymptomatic controls, only Reprimo was infrequently methylated in comparison with plasma from gastric cancer cases (P < 0.001).Conclusion: Our results identified specific methylation profile associated to signet-ring cell-type histology and aberrant hypermethylation of Reprimo as a potential biomarker for early detection of gastric cancer.