Promoter hypermethylation profile of ovarian epithelial neoplasms
Promoter hypermethylation profile of ovarian epithelial neoplasms
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DOI：
10.1158/1078-0432.ccr-04-2455
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发表时间：
2005-08-01
影响因子：
11.5
通讯作者：
Schorge, JO
中科院分区：
文献类型：
--
作者：
Makarla, PB;Saboorian, MH;Schorge, JO
目的：卵巢癌被认为是由表面上皮从头产生的，但实际的分子发病机制尚不清楚。本研究的目的是比较卵巢上皮肿瘤的启动子高甲基化谱，以更好地了解表观遗传沉默在癌发生中的作用。 实验设计：我们分析了 23 例良性囊腺瘤、23 例低度恶性潜能的 8 个肿瘤抑制基因和癌症相关基因（p16、RAR beta、E-钙粘蛋白 H-钙粘蛋白、APC、GSTP1、MGMT、RASSF1A）的 DNA 启动子甲基化状态(LMP) 肿瘤和 23 个浸润性癌通过甲基化特异性 PCR 进行检测。结果：良性囊腺瘤仅在两个基因中表现出启动子高甲基化：p16 (13%) 和 E-cadherin (13%)。除了 RAR β (9%) 和 H-钙粘蛋白 (4%) 之外，LMP 肿瘤还显示 p16 (22%) 和 E-钙粘蛋白 (17%) 甲基化。所有八个基因在侵袭性癌症中均发生高甲基化，发生频率为 9% 至 30%。平均甲基化指数在侵袭性肿瘤中最高[0.20 vs 0.065（LMP）和0.033（囊腺瘤）； P = 0.001]。至少一个基因的启动子甲基化在侵袭性癌症中最常见[78% vs 44%（LMP；P = 0.03）和26%（囊腺瘤；P = 0.0009）]。三个基因在侵袭性肿瘤中表现出较高的甲基化频率：RASSF1A（30% 与 0%；P = 0.0002）、H-钙粘蛋白（22% 与 2%；P = 0.013）和 APC（22% 与 0%；P = 0.003）。 结论：启动子高甲基化是一种常见的表观遗传事件，最常见于侵袭性上皮性卵巢癌。异常甲基化的概况表明，特定基因事件的积累可能会引发一些良性囊肿和 LMP 肿瘤的恶性转化。
Purpose: Ovarian carcinomas are believed to arise de novo from surface epithelium, but the actual molecular pathogenesis is unknown. The aim of this study was to compare the promoter hypermethylation profiles of ovarian epithelial neoplasms to better understand the role of epigenetic silencing in carcinogenesis.Experimental Design: We analyzed the DNA promoter methylation status of eight tumor suppressor and cancer-related genes (p16, RAR beta, E-cadherin H-cadherin, APC, GSTP1, MGMT, RASSF1A) in 23 benign cystadenomas, 23 low malignant potential (LMP) tumors, and 23 invasive carcinomas by methylation-specific PCR.Results: Benign cystadenomas exhibited promoter hypermethylation in only two genes, p16 (13%) and E-cadherin (13%). LMP tumors also showed p16 (22%) and E-cadherin (17%) methylation, in addition to RAR beta (9%) and H-cadherin (4%). All eight genes were hypermethylated in invasive cancers at a frequency of 9% to 30%. The mean methylation index was highest in invasive tumors [0.20 versus 0.065 (LMP) and 0,033 (cystadenomas); P = 0.001]. Promoter methylation of at least one gene was most commonly observed among invasive cancers [78% versus 44% (LMP; P = 0.03) and 26% (cystadenomas; P = 0.0009)]. Three genes exhibited higher methylation frequencies in invasive tumors: RASSF1A (30% versus 0%; P = 0.0002), H-cadherin (22% versus 2%; P = 0.013), and APC (22% versus 0%; P = 0.003).Conclusions: Promoter hypermethylation is a frequent epigenetic event that occurs most commonly in invasive epithelial ovarian carcinomas. The profile of aberrant methylation suggests that an accumulation of events at specific genes may trigger malignant transformation of some benign cystaclenomas and LMP tumors.