Transcriptome and DNA methylation analyses highlight the role of menstrual cycle phase in tumorigenesis of endometriosis-related ovarian carcinoma histotypes [methylation]

Epithelial ovarian cancer, or ovarian carcinoma (OC), is a diverse disease. Two of the rarer subtypes, clear cell OC (CCOC) and endometrioid OC (ENOC), both arise from ovarian endometriotic cysts, particularly atypical endometriosis. CCOC and ENOC have similar mutation profiles and share a common cell of origin, but their cellular phenotypes and clinical outcomes are distinct; in particular, CCOC has poor clinical survival. The most well-known difference between the histotypes is the universal overexpression of HNF1B (Hepatocyte nuclear factor-1β) in clear cell tumors and overexpression of ESR1 in ENOC. It is not well understood how these discrete histotypes arise from the same cell of origin. Via transcriptional (n=57) and DNA methylation analysis (N=127) of these rare tumors, we show that CCOC closely resembles secretory endometrium in transcriptional profile; whereas ENOC transcriptomes resemble proliferative endometrium. This dataset represnts 127 samples profiled by 450K methylation array. The samples are from ovarian tumor subtypes: clear cell (N=19), endometrioid (N=48), and high-grade serous (N=60).

上皮性卵巢癌，又称卵巢癌（OC），是一类异质性极强的疾病。其中两种较为罕见的亚型——透明细胞型卵巢癌（CCOC）与子宫内膜样型卵巢癌（ENOC），均起源于卵巢子宫内膜异位囊肿，尤其与不典型子宫内膜异位症相关。二者具有相似的突变谱且共享同一细胞起源，但细胞表型与临床结局却存在显著差异；其中透明细胞型卵巢癌的临床生存率尤为低下。两类组织学亚型最广为人知的差异在于：透明细胞肿瘤普遍过表达肝细胞核因子1β（HNF1B，Hepatocyte nuclear factor-1β），而ENOC则普遍过表达ESR1。目前学界对于这两种起源相同的组织学亚型为何会呈现出截然不同的表型仍知之甚少。本研究通过对这类罕见肿瘤进行转录组分析（样本量n=57）与DNA甲基化分析（样本量N=127），发现透明细胞型卵巢癌的转录谱与分泌期子宫内膜高度相似，而子宫内膜样型卵巢癌的转录组则类似于增殖期子宫内膜。本数据集共包含127份经450K甲基化芯片检测的样本，这些样本分别来自三种卵巢肿瘤亚型：透明细胞型（N=19）、子宫内膜样型（N=48）以及高级别浆液性癌（N=60）。