title: Epigenetic analysis of sporadic and Lynch-associated ovarian cancers reveals histology-specific patterns of DNA methylation.
abstract: 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.
authors.affiliation: a Department of Medical Genetics; Biomedicum Helsinki ; University of Helsinki ; Helsinki , Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Niskakoski
authors.forename: Sippy
authors.initials: S
authors.lastname: Kaur
authors.forename: Synnöve
authors.initials: S
authors.lastname: Staff
authors.forename: Laura
authors.initials: L
authors.lastname: Renkonen-Sinisalo
authors.forename: Heini
authors.initials: H
authors.lastname: Lassus
authors.forename: Heikki J
authors.initials: HJ
authors.lastname: Järvinen
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D018269:Carcinoma, Endometrioid / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics; D010051:Ovarian Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D012016:Reference Values
chemical_list: D014408:Biomarkers, Tumor
keywords: DNA methylation; Dm, methylation dosage ratio; HOXA9; LS, Lynch syndrome; Lynch syndrome; MS-MLPA ovarian cancer; MS-MLPA, methylation-specific multiplex ligation-dependent probe amplification; RSK4; SPARC; TSG, tumor suppressor gene; WT1, Wilms tumor suppressor 1 sense; WT1-AS, Wilms tumor suppressor 1 antisense; epigenetics; miRNAs, microRNAs