Epigenetic analysis of sporadic and Lynch-associated ovarian cancers reveals histology-specific patterns of DNA methylation.
Epigenetic analysis of sporadic and Lynch-associated ovarian cancers reveals histology-specific patterns of DNA methylation.
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DOI：
10.4161/15592294.2014.983374
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发表时间：
2014-12
期刊：
影响因子：
3.7
通讯作者：
Peltomäki P
中科院分区：
文献类型：
--
作者：
Niskakoski A;Kaur S;Staff S;Renkonen-Sinisalo L;Lassus H;Järvinen HJ;Mecklin JP;Bützow R;Peltomäki P
上皮性卵巢癌的诊断和治疗是具有挑战性的，由于对疾病的发病机制的认识不足。我们的目的是研究卵巢肿瘤发生的表观遗传机制，特别是不同组织学亚型或遗传背景（Lynch综合征）的肿瘤是否对生长调节基因的表观遗传失活表现出不同的易感性。表观遗传调控的候选基因是从文献中以及通过用去甲基化剂处理的卵巢癌和子宫内膜癌细胞系的表达谱来鉴定的。选择13个基因对104例（85例散发性和19例Lynch综合征相关）卵巢癌进行甲基化特异性多重连接依赖性探针扩增测定。增加的甲基化（即，相对于相应的正常组织，不同程度的高甲基化（高甲基化）是卵巢癌的特征，对于所研究的单个基因和基因组，高甲基化在非浆液性肿瘤中始终比浆液性肿瘤更突出。Lynch综合征相关的透明细胞癌表现出最高的甲基化频率。在子宫内膜样卵巢癌中，RSK 4、SPARC和HOXA 9启动子甲基化水平较低与肿瘤级别较高显着相关;因此，甲基化模式显示出向高级别浆液性肿瘤方向的转变。总之，我们提供的证据表明，与浆液性肿瘤相比，在Lynch和散发性来源的非浆液性卵巢癌的发展中，RSK 4、PRK、PROM 1、HOXA 10、HOXA 9、WT 1-AS、SFRP 2、SFRP 5、OPCML和MIR 34 B的表观遗传失活频繁。我们的发现揭示了表观遗传机制在卵巢肿瘤发生中的作用，并确定了翻译应用的潜在靶点。
Diagnosis and treatment of epithelial ovarian cancer is challenging due to the poor understanding of the pathogenesis of the disease. Our aim was to investigate epigenetic mechanisms in ovarian tumorigenesis and, especially, whether tumors with different histological subtypes or hereditary background (Lynch syndrome) exhibit differential susceptibility to epigenetic inactivation of growth regulatory genes. Gene candidates for epigenetic regulation were identified from the literature and by expression profiling of ovarian and endometrial cancer cell lines treated with demethylating agents. Thirteen genes were chosen for methylation-specific multiplex ligation-dependent probe amplification assays on 104 (85 sporadic and 19 Lynch syndrome-associated) ovarian carcinomas. Increased methylation (i.e., hypermethylation) of variable degree was characteristic of ovarian carcinomas relative to the corresponding normal tissues, and hypermethylation was consistently more prominent in non-serous than serous tumors for individual genes and gene sets investigated. Lynch syndrome-associated clear cell carcinomas showed the highest frequencies of hypermethylation. Among endometrioid ovarian carcinomas, lower levels of promoter methylation of RSK4, SPARC, and HOXA9 were significantly associated with higher tumor grade; thus, the methylation patterns showed a shift to the direction of high-grade serous tumors. In conclusion, we provide evidence of a frequent epigenetic inactivation of RSK4, SPARC, PROM1, HOXA10, HOXA9, WT1-AS, SFRP2, SFRP5, OPCML, and MIR34B in the development of non-serous ovarian carcinomas of Lynch and sporadic origin, as compared to serous tumors. Our findings shed light on the role of epigenetic mechanisms in ovarian tumorigenesis and identify potential targets for translational applications.