USC Epigenome Center, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
Nat Commun. 2013;4:1628. doi: 10.1038/ncomms2629.
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
HNF1B 在透明细胞卵巢上皮癌中过表达，而我们在浆液性卵巢上皮癌中观察到表观遗传沉默，这使我们假设该基因的变异根据组织学亚型与卵巢上皮癌风险存在差异关联。在这里，我们全面研究了 HNF1B 与卵巢上皮癌风险的变异，并分析了不同组织学亚型的 DNA 甲基化和表达谱。不同的单核苷酸多态性与侵袭性浆液性（rs7405776 比值比（OR）=1.13，P=3.1×10(-10)）和透明细胞（rs11651755 OR=0.77，P=1.6×10(-8)）卵巢上皮癌有关。浆液性肿瘤中，与风险相关的单核苷酸多态性与 HNF1B 启动子更高的甲基化有关。未甲基化、表达的 HNF1B 主要存在于透明细胞肿瘤中，与影响基因组中许多其他启动子的 CpG 岛甲基化表型一致。HNF1B 中的不同变体与浆液性和透明细胞卵巢上皮癌的风险相关；这些亚型之间的 DNA 甲基化和表达模式也明显不同。这些发现强调了驱动不同卵巢上皮癌组织学亚型的不同机制。
