Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia.
Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia.
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DOI：
10.1007/s11605-008-0633-5
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发表时间：
2008-10
影响因子：
3.2
通讯作者：
Ahuja, Nita
中科院分区：
文献类型：
--
作者：
Dhir, Mashaal;Montgomery, Elizabeth A.;Glockner, Sabine C.;Schuebel, Kornel E.;Hooker, Craig M.;Herman, James G.;Baylin, Stephen B.;Gearhart, Susan L.;Ahuja, Nita
WNT 信号通路失调是结直肠癌 (CRC) 发病机制中的一个重要事件，超过 80% 的散发性 CRC 中存在 APC 突变。然而，WNT 信号通路基因的此类突变在炎症性肠病 (IBD) 相关肿瘤（不典型增生和癌症）中很少见。本研究探讨了 WNT 信号通路基因的表观遗传沉默在 IBD 相关肿瘤发病机制中的作用。获得石蜡包埋的组织样本，并分析 10 个 WNT 信号通路基因的甲基化，包括 APC1A、APC2、SFRP1、SFRP2、SFRP4、SFRP5、DKK1、DKK3、WIF1 和 LKB1。对 41 个 IBD 样本、27 个正常结肠样本 (NC) 和 24 个散发的 CRC 样本进行甲基化分析。 WNT 信号通路基因的甲基化是 IBD 和 IBD 相关肿瘤中常见的早期事件。 WNT 信号通路中甲基化基因的百分比从 NC（4.2%）到 IBD 结肠炎（39.7%）再到 IBD 相关肿瘤（63.4%）逐渐增加（NC 与 IBD 结肠炎，p<0.01；IBD 结肠炎与 IBD 相关肿瘤，p=0.01）。在单变量逻辑回归模型中，APC2（OR 4.7，95% CI：1.1-20.63，p=0.04）、SFRP1（OR 5.1，95% CI：1.1-31.9，p=0.04）和 SFRP2（OR 5.1，95% CI：1.1-32.3，p=0.04）的甲基化与 IBD 结肠炎进展为 IBD 相关肿瘤相关，而 APC1A 甲基化具有临界显着性（OR 4.1，95% CI：0.95–17.5，p=0.06）。在多变量逻辑回归模型中，APC1A 和 APC2 的甲基化更有可能与 IBD 相关肿瘤相关，而不是与 IBD 结肠炎相关。 （或 APC1A：6.4，95% CI：1.1–37.7，p=0.04；或 APC2 9.1，95% CI：1.3–61.7，p=0.02）。 WNT 信号基因的甲基化是 IBD 结肠炎患者中观察到的早期事件，并且在 IBD 相关肿瘤的发展过程中 WNT 信号基因的甲基化逐渐增加。此外，APC1A、APC2、SFRP1和SFRP2的甲基化似乎标志着从IBD结肠炎到IBD相关肿瘤的进展，并且这些基因可以作为IBD相关肿瘤的生物标志物。
WNT signaling pathway dysregulation is an important event in the pathogenesis of colorectal cancer (CRC) with APC mutations seen in more than 80% of sporadic CRC. However, such mutations in the WNT signaling pathway genes are rare in inflammatory bowel disease (IBD) associated neoplasia (dysplasia and cancer). This study examined the role of epigenetic silencing of WNT signaling pathway genes in the pathogenesis of IBD-associated neoplasia. Paraffin-embedded tissue samples were obtained and methylation of ten WNT signaling pathway genes, including APC1A, APC2, SFRP1, SFRP2, SFRP4, SFRP5, DKK1, DKK3, WIF1 and LKB1, was analyzed. Methylation analysis was performed on 41 IBD samples, 27 normal colon samples (NCs), and 24 sporadic CRC samples. Methylation of WNT signaling pathway genes is a frequent and early event in IBD and IBD-associated neoplasia. A progressive increase in the percentage of methylated genes in the WNT signaling pathway from NCs (4.2%) to IBD colitis (39.7%) to IBD-associated neoplasia (63.4%) was seen (NCs vs. IBD colitis, p<0.01; IBD colitis vs. IBD-associated neoplasia, p=0.01). In the univariate logistic regression model, methylation of APC2 (OR 4.7, 95% CI: 1.1–20.63, p=0.04), SFRP1 (OR 5.1, 95% CI: 1.1–31.9, p=0.04), and SFRP2 (OR 5.1, 95% CI: 1.1–32.3, p=0.04) was associated with progression from IBD colitis to IBD-associated neoplasia, while APC1A methylation was borderline significant (OR 4.1, 95% CI: 0.95–17.5, p=0.06). In the multivariate logistic regression model, methylation of APC1A and APC2 was more likely to be associated with IBD-associated neoplasia than IBD colitis. (OR APC1A: 6.4, 95% CI: 1.1–37.7 p=0.04; OR APC2 9.1, 95% CI: 1.3–61.7, p=0.02). Methylation of the WNT signaling genes is an early event seen in patients with IBD colitis and there is a progressive increase in methylation of the WNT signaling genes during development of IBD-associated neoplasia. Moreover, methylation of APC1A, APC2, SFRP1, and SFRP2 appears to mark progression from IBD colitis to IBD-associated neoplasia, and these genes may serve as biomarkers for IBD-associated neoplasia.
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影响因子：
7.5
作者：
Aust, DE;Terdiman, TP;Waldman, FM
通讯作者：
Waldman, FM
影响因子：
4.8
作者：
Bafico, A;Gazit, A;Aaronson, SA
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29.4
作者：
BRENTNALL, TA;CRISPIN, DA;BURMER, GC
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BURMER, GC
影响因子：
29.4
作者：
CHOI, PM;NUGENT, FW;HAGGITT, RC
通讯作者：
HAGGITT, RC
影响因子：
4.9
作者：
Hanauer, SB
通讯作者：
Hanauer, SB