Background: Changes in DNA methylation patterns are a pivotal mechanism of carcinogenesis. In some tumors, aberrant methylation precedes genetic changes, while gene expression may be more frequently modified due to methylation alterations than by mutations.Methods: Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) theBRAFV600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays.Results: The biggest number of differentially methylated (DM) CpGs and regions (DMRs) was found between lgOvCa and hgOvCa. By contrast, the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups and, in relation to BOT, their genome was strongly downmethylated. Remarkably, the ten most significant DMRs, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs, being of potential use as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes:BAIAP3,IL34,WNT10A,NEU1,SLC44A4,andHMOX1,TCN2,PES1,RP1-56J10.8,ABR,NCAM1,RP11-629G13.1,AC006372.4,NPTXRin BOTS and hgOvCa, respectively.Conclusions: The global genome-wide hypomethylation positively correlates with the increasing aggressiveness of ovarian tumors. We also assume that the immune system may play a pivotal role in the transition from BOTS to lgOvCa. Given that the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups, when methylome is considered, such tumors might be placed in-between BOT and OvCa.
背景：DNA甲基化模式的改变是致癌的关键机制。在某些肿瘤中，异常甲基化先于遗传变化发生，且甲基化改变对基因表达的影响可能比突变更为频繁。 方法：本研究分析了128例浆液性卵巢肿瘤，包括携带BRAF V600E突变（BOT.V600E）和不携带该突变（BOT）的卵巢交界性肿瘤（BOTS）、低级别（lg）和高级别（hg）卵巢癌（OvCa）。使用Infinium MethylationEPIC微阵列芯片对样本进行全基因组甲基化谱分析。 结果：在lgOvCa与hgOvCa之间发现了最多数量的差异甲基化（DM）CpG位点和差异甲基化区域（DMRs）。相比之下，BOT.V600E肿瘤在所有组别中具有最少的DM CpG位点和DMRs，并且与BOT相比，其基因组呈现显著的低甲基化状态。值得注意的是，区分BOT与lgOvCa的十个最显著DMRs涵盖了染色体6上的MHC区域。我们还鉴定出数百个DMRs，这些区域在BOTS和hgOvCa中具有作为预测性生物标志物的潜在价值。区分能力最佳的DMRs与以下基因重叠：在BOTS中为BAIAP3、IL34、WNT10A、NEU1、SLC44A4及HMOX1；在hgOvCa中为TCN2、PES1、RP1-56J10.8、ABR、NCAM1、RP11-629G13.1、AC006372.4、NPTXR。 结论：全基因组范围内的低甲基化与卵巢肿瘤侵袭性的增强呈正相关。我们同时认为免疫系统可能在BOTS向lgOvCa的转化过程中发挥关键作用。鉴于BOT.V600E肿瘤在所有组别中具有最少的DM CpG位点和DMRs，从甲基化组的角度考虑，此类肿瘤可能处于BOT与OvCa之间的过渡状态。
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