宫颈癌(CC)是全球女性癌症死亡的第二大原因。通过DNA甲基化和羟甲基化对基因表达的表观遗传调节在肿瘤发生中起着关键作用。在这项研究中,分析表观基因组景观并确定CC的潜在生物标志物,我们选择了从正常到宫颈上皮内瘤变(CIN)到CC的一系列样本,并进行了全基因组亚硫酸氢盐测序(WGBS-seq)的综合分析,氧化性WGBS,RNA-seq,和外部组蛋白修饰分析数据。
在CC的发展和进步中,存在全基因组低甲基化和低羟甲基化,伴有局部超甲基化和超羟甲基化。羟甲基化倾向于分布在CpG岛和CpG海岸,显示出从健康到CIN2逐渐下降的趋势,而从CIN3到CC的趋势增加。差异甲基化和羟甲基化区域相关基因都富含Hippo和其他驱动宫颈癌发生的癌症相关信号通路。此外,我们确定了八个新的差异甲基化/羟甲基化相关基因(DES,MAL,MTIF2,PIP5K1A,RPS6KA6,ANGEL2,MPP,和PAPSS2)与CC的总体生存率显着相关。此外,在CINs和CC中,甲基化或羟甲基化水平与体细胞拷贝数变异之间未观察到任何相关性.
我们目前的研究系统地描绘了从CIN到CC的甲基化和羟甲基化的图谱,一些差异甲基化/羟甲基化相关基因可作为CC预后的潜在表观遗传生物标志物。
Cervical cancer (CC) is the second leading cause of cancer death among women worldwide. Epigenetic regulation of gene expression through DNA methylation and hydroxymethylation plays a pivotal role during tumorigenesis. In this study, to analyze the epigenomic landscape and identify potential biomarkers for CCs, we selected a series of samples from normal to cervical intra-epithelial neoplasia (CINs) to CCs and performed an integrative analysis of whole-genome bisulfite sequencing (WGBS-seq), oxidative WGBS, RNA-seq, and external histone modifications profiling data.
In the development and progression of CC, there were genome-wide hypo-methylation and hypo-hydroxymethylation, accompanied by local hyper-methylation and hyper-hydroxymethylation. Hydroxymethylation prefers to distribute in the CpG islands and CpG shores, as displayed a trend of gradual decline from health to CIN2, while a trend of increase from CIN3 to CC. The differentially methylated and hydroxymethylated region-associated genes both enriched in Hippo and other cancer-related signaling pathways that drive cervical carcinogenesis. Furthermore, we identified eight novel differentially methylated/hydroxymethylated-associated genes (DES, MAL, MTIF2, PIP5K1A, RPS6KA6, ANGEL2, MPP, and PAPSS2) significantly correlated with the overall survival of CC. In addition, no any correlation was observed between methylation or hydroxymethylation levels and somatic copy number variations in CINs and CCs.
Our current study systematically delineates the map of methylome and hydroxymethylome from CINs to CC, and some differentially methylated/hydroxymethylated-associated genes can be used as the potential epigenetic biomarkers in CC prognosis.