Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome.
Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome.
复制标题
DOI：
10.1186/1476-4598-2-24
复制
发表时间：
2003-05-13
期刊：
影响因子：
37.3
通讯作者：
Murty VV
中科院分区：
文献类型：
--
作者：
Narayan G;Arias-Pulido H;Koul S;Vargas H;Zhang FF;Villella J;Schneider A;Terry MB;Mansukhani M;Murty VV
宫颈癌(CC)是全球女性癌症相关死亡的主要原因，与生殖器人类乳头瘤病毒(HPV)感染有因果关系。虽然已经鉴定了大量的基因改变，但CC发生的分子基础仍然知之甚少。我们通过研究90例CC中的16个基因启动子，研究了启动子超甲基化的作用，这是一种与人类癌症中沉默抑癌基因相关的表观遗传学改变。我们在CDH1、DAPK、RARB和HIC1基因中发现了高频率的启动子甲基化。启动子甲基化与临床特征和其他遗传改变的相关性显示：a)在疾病的晚期，总的启动子甲基化水平较高，b)RARB和BRCA1启动子甲基化预示着较差的预后，c)HIC1启动子甲基化与微卫星不稳定性有关。在CC细胞系中，启动子甲基化与基因沉默有关。甲基化或组蛋白去乙酰化抑制药治疗导致基因表达的显著重新激活。这些结果可能对理解CC发生的潜在表观遗传学机制，提供预后指标，并确定重要的治疗基因靶点具有重要意义。
Cervical cancer (CC), a leading cause of cancer-related deaths in women worldwide, has been causally linked to genital human papillomavirus (HPV) infection. Although a host of genetic alterations have been identified, molecular basis of CC development is still poorly understood. We examined the role of promoter hypermethylation, an epigenetic alteration that is associated with the silencing tumor suppressor genes in human cancer, by studying 16 gene promoters in 90 CC cases. We found a high frequency of promoter methylation in CDH1, DAPK, RARB, and HIC1 genes. Correlation of promoter methylation with clinical characteristics and other genetic changes revealed the following: a) overall promoter methylation was higher in more advanced stage of the disease, b) promoter methylation of RARB and BRCA1 predicted worse prognosis, and c) the HIC1 promoter methylation was frequently seen in association with microsatellite instability. Promoter methylation was associated with gene silencing in CC cell lines. Treatment with methylation or histone deacetylation-inhibiting agents resulted in profound reactivation of gene expression. These results may have implications in understanding the underlying epigenetic mechanisms in CC development, provide prognostic indicators, and identify important gene targets for treatment.