Makarla Prakash B, Saboorian M Hossein, Ashfaq Raheela, Toyooka Kiyomi O, Toyooka Shinichi, Minna John D, Gazdar Adi F, Schorge John O
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Clin Cancer Res. 2005 Aug 1;11(15):5365-9. doi: 10.1158/1078-0432.CCR-04-2455.
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.
We analyzed the DNA promoter methylation status of eight tumor suppressor and cancer-related genes (p16, RARbeta, 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.
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 RARbeta (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).
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 cystadenomas and LMP tumors.
卵巢癌被认为起源于表面上皮的新生肿瘤，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性肿瘤的启动子高甲基化谱，以更好地了解表观遗传沉默在致癌作用中的作用。
我们通过甲基化特异性PCR分析了23例良性囊腺瘤、23例低恶性潜能（LMP）肿瘤和23例浸润性癌中8个肿瘤抑制基因和癌症相关基因（p16、RARβ、E-钙黏蛋白、H-钙黏蛋白、APC、GSTP1、MGMT、RASSF1A）的DNA启动子甲基化状态。
良性囊腺瘤仅在两个基因中表现出启动子高甲基化，即p16（13%）和E-钙黏蛋白（13%）。LMP肿瘤除了RARβ（9%）和H-钙黏蛋白（4%）甲基化外，还显示p16（22%）和E-钙黏蛋白（17%）甲基化。所有8个基因在浸润性癌中的高甲基化频率为9%至30%。平均甲基化指数在浸润性肿瘤中最高[0.20对比0.065（LMP）和0.033（囊腺瘤）；P = 0.001]。在浸润性癌中最常观察到至少一个基因的启动子甲基化[78%对比44%（LMP；P = 0.03）和26%（囊腺瘤；P = 0.0009）]。三个基因在浸润性肿瘤中表现出更高的甲基化频率：RASSF1A（30%对比0%；P = 0.0002）、H-钙黏蛋白（22%对比2%；P = 0.013）和APC（22%对比0%；P = 0.003）。
启动子高甲基化是一种常见的表观遗传事件，最常发生在浸润性上皮性卵巢癌中。异常甲基化谱表明特定基因处事件的积累可能触发一些良性囊腺瘤和LMP肿瘤的恶性转化。
