DNA methylation as an adjunct to histopathology to detect prevalent, inconspicuous dysplasia and early-stage neoplasia in Barrett's esophagus.
DNA methylation as an adjunct to histopathology to detect prevalent, inconspicuous dysplasia and early-stage neoplasia in Barrett's esophagus.
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DOI：
10.1158/1078-0432.ccr-12-2880
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发表时间：
2013-02-15
期刊：
影响因子：
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通讯作者：
Fitzgerald RC
中科院分区：
文献类型：
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作者：
Alvi MA;Liu X;O'Donovan M;Newton R;Wernisch L;Shannon NB;Shariff K;di Pietro M;Bergman JJ;Ragunath K;Fitzgerald RC
Barrett‘s食道(BE)的内窥镜监测是有问题的，因为异型增生/早期肿瘤通常是看不见的，并且由于抽样偏差而很可能被遗漏。分子异常可能比异型增生更弥漫。因此，目的是测试DNA甲基化，特别是印记和X染色体基因上的甲基化是否能够检测出异型增生/早期肿瘤。用27K甲基化芯片寻找能够区分22例BE和24例食管腺癌(EAC)的基因。在一组回溯性队列(60例BE，36例发育不良和90例EAC)和一项前瞻性多中心研究(98例BE患者，包括28例发育不良和9例早期EAC)中，利用生物标记物根据患者普遍的异型增生/EAC状况对患者进行分层，验证了这些研究的有效性。阵列上23%的基因，包括7%的X连锁基因和69%的印迹基因，在EAC和BE中显示出统计学上显著的甲基化变化(Wilcoxon P<；0.05)。选择的候选基因中有6/7在内部(Pearson‘s P<；0.01)和外部验证(ANOVA P<；0.001)获得成功。4个基因(SLC22A18、PIGR、GJA12和RIN2)在回溯性队列中显示最大的曲线下面积(0.988)来区分BE和异型增生/EAC。这个甲基化小组能够根据甲基化基因的数量将前瞻性队列中的患者分成三个风险组(低风险：2个基因，中级：2个，高风险：2个)。在巴雷特的癌变过程中观察到了广泛的DNA甲基化变化，其中包括70%的已知印迹基因的≈。一个由四个基因甲基化组成的小组将BE患者分为三个风险组，具有潜在的临床实用价值。
Endoscopic surveillance of Barrett’s esophagus (BE) is problematic because dysplasia/early-stage neoplasia are frequently invisible and likely to be missed due to sampling bias. Molecular abnormalities may be more diffuse than dysplasia. The aim was therefore to test whether DNA methylation; especially on imprinted and X-chromosome genes; is able to detect dysplasia/early-stage neoplasia. 27K methylation arrays were used to find genes best able to differentiate between 22 BE and 24 esophageal adenocarcinoma (EAC) samples. These were validated using pyrosequencing on a retrospective cohort (60 BE, 36 dysplastic and 90 EAC) and then in a prospective multicenter study (98 BE patients, including 28 dysplastic and 9 early EAC) designed to utilize biomarkers to stratify patients according to their prevalent dysplasia/EAC status. 23% genes on the array, including 7% of X-linked and 69% of imprinted genes, demonstrated statistically significant changes in methylation in EAC vs. BE (Wilcoxon P<0.05). 6/7 selected candidate genes were successfully internally (Pearson’s P<0.01) and externally validated (ANOVA P<0.001). Four genes (SLC22A18, PIGR, GJA12 and RIN2) showed the greatest area under curve (0.988) to distinguish between BE and dysplasia/EAC in the retrospective cohort. This methylation panel was able to stratify patients from the prospective cohort into three risk groups based on the number of genes methylated (low risk: <2 genes, intermediate: 2 and high: >2). Widespread DNA methylation changes were observed in Barrett’s carcinogenesis including ≈70% of known imprinted genes. A four-gene methylation panel stratified BE patients into three risk groups with potential clinical utility.