Reid Brett M, Fridley Brooke L
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Cancers (Basel). 2020 Dec 31;13(1):108. doi: 10.3390/cancers13010108.
Epigenetic alterations are somatically acquired over the lifetime and during neoplastic transformation but may also be inherited as widespread 'constitutional' alterations in normal tissues that can cause cancer predisposition. Epithelial ovarian cancer (EOC) has an established genetic susceptibility and mounting epidemiological evidence demonstrates that DNA methylation (DNAm) intermediates as well as independently contributes to risk. Targeted studies of known EOC susceptibility genes (CSGs) indicate rare, constitutional promoter methylation increases familial and sporadic EOC risk. Blood-based epigenome-wide association studies (EWAS) for EOC have detected a total of 2846 differentially methylated probes (DMPs) with 71 genes replicated across studies despite significant heterogeneity. While EWAS detect both symptomatic and etiologic DMPs, adjustments and analytic techniques may enrich risk associations, as evidenced by the detection of dysregulated methylation of -a known CSG identified by genome-wide associations studies (GWAS). Integrative genetic-epigenetic approaches have mapped methylation quantitative trait loci (meQTL) to EOC risk, revealing DNAm variations that are associated with nine GWAS loci and, further, one novel risk locus. Increasing efforts to mapping epigenome variation across populations and cell types will be key to decoding both the genomic and epigenomic causal pathways to EOC.
表观遗传改变是在个体一生中以及肿瘤转化过程中体细胞获得的，但也可能作为正常组织中广泛存在的“构成性”改变而遗传，这些改变可导致癌症易感性。上皮性卵巢癌（EOC）具有明确的遗传易感性，越来越多的流行病学证据表明，DNA甲基化（DNAm）中间体以及独立因素均对风险有影响。对已知的EOC易感基因（CSG）进行的靶向研究表明，罕见的、构成性的启动子甲基化会增加家族性和散发性EOC风险。针对EOC的基于血液的全表观基因组关联研究（EWAS）共检测到2846个差异甲基化探针（DMP），尽管存在显著异质性，但有71个基因在各研究中得到重复。虽然EWAS可检测有症状和病因性的DMP，但调整和分析技术可能会丰富风险关联，如对通过全基因组关联研究（GWAS）确定的一个已知CSG的甲基化失调的检测所证明的那样。综合遗传 - 表观遗传方法已将甲基化数量性状位点（meQTL）映射到EOC风险，揭示了与9个GWAS位点相关的DNAm变异，此外还有一个新的风险位点。加大努力绘制不同人群和细胞类型的表观基因组变异图谱，将是解码EOC基因组和表观基因组因果途径的关键。
