High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer, with a poor prognosis; however, most studies concerning ovarian carcinoma have focused mainly on clear cell carcinoma. The involvement of hepatocyte nuclear factor 1β (HNF1B) in the carcinogenesis of HGSC has not yet been fully elucidated. To the best of our knowledge, the present study is the first to analyse the expression of the possible downstream target of HNF1B, enoyl-CoA (Δ) isomerase 2 (ECI2), in HGSC. The present study performed a comprehensive analysis of HNF1B mRNA and protein expression, and epigenetic and genetic changes, as well as an analysis of ECI2 mRNA and protein expression in 122 cases of HGSC. HNF1B protein expression was detected in 28/122 cases, and was positively associated with lymphovascular invasion (P=0.025). Protein expression of ECI2 was detected in 115/122 cases, but no associations with clinicopathological variables were revealed. Therefore, ECI2 does not seem to function as a suitable prognostic marker for HGSC. In the sample set, a positive correlation between HNF1B and ECI2 protein expression was detected (P=0.005). HNF1B mRNA was also positively correlated with HNF1B protein expression (P=0.001). HNF1B promoter methylation was detected in 26/67 (38.8%) of cases. A novel pathogenic somatic HNF1B mutation was detected in 1/61 (1.6%) of the analysed HGSC cases. No other correlations between the examined SNPs (rs4430796, rs757210 and rs7405776), HNF1B promoter methylation, HNF1B/ECI2 expression or clinicopathological characteristics were found.

• Klíčová slova
• enoyl-CoA (Δ) isomerase 2, hepatocyte nuclear factor 1β, high-grade serous carcinoma, immunohistochemistry, mRNA, methylation, mutation analysis, ovarian carcinoma,
• Publikační typ
• časopisecké články MeSH

Hepatocyte nuclear factor 1 beta (HNF1B) is a transcription factor which plays a crucial role in nephronogenesis, and its germline mutations have been associated with kidney developmental disorders. However, the effects of HNF1B somatic exonic mutations and its role in the pathogenesis of kidney tumours has not yet been elucidated. Depending on the type of the tumour HNF1B may act as a tumour suppressor or oncogene, although the exact mechanism by which HNF1B participates in the process of cancerogenesis is unknown. Using an immunohistochemical approach, and methylation and mutation analysis, we have investigated the expression, epigenetic, and genetic changes of HNF1B in 130 cases of renal tumours (121 renal cell carcinomas, 9 oncocytomas). In the subset of clear cell renal cell carcinoma (ccRCC), decreased HNF1B expression was associated with a higher tumour grade and higher T stage. The mutation analysis revealed no mutations in the analysed samples. Promoter methylation was detected in two ccRCCs and one oncocytoma. The results of our work on a limited sample set suggest that while in papillary renal cell carcinoma HNF1B functions as an oncogene, in ccRCC and chRCC it may act in a tumour suppressive fashion.

• MeSH
• epigeneze genetická genetika   MeSH
• epigenomika metody   MeSH
• hepatocytární jaderný faktor 1-beta genetika   MeSH
• karcinom z renálních buněk genetika   patologie   MeSH
• ledviny patologie   MeSH
• lidé MeSH
• mutační analýza DNA metody   MeSH
• nádory ledvin genetika   patologie   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-beta MeSH
• HNF1B protein, human MeSH Prohlížeč

Hepatocyte nuclear factor 1 beta (HNF1B) is a tissue specific transcription factor, which seems to play an important role in the carcinogenesis of several tumors. In our study we focused on analyzing HNF1B in prostate carcinoma (PC) and adenomyomatous hyperplasia (AH), as well as its possible relation to the upstream gene EZH2 and downstream gene ECI2. The results of our study showed that on an immunohistochemical level, the expression of HNF1B was low in PC, did not differ between PC and AH, and did not correlate with any clinical outcomes. In PC, mutations of HNF1B gene were rare, but the methylation of its promotor was a common finding and was positively correlated with Gleason score and stage. The relationship between HNF1B and EZH2/ECI2 was equivocal, but EZH2 and ECI2 were positively correlated on both mRNA and protein level. The expression of EZH2 was associated with poor prognosis. ECI2 did not correlate with any clinical outcomes. Our results support the oncosuppressive role of HNF1B in PC, which may be silenced by promotor methylation and other mechanisms, but not by gene mutation. The high expression of EZH2 (especially) and ECI2 in PC seems to be a potential therapeutic target.

• MeSH
• enoyl-CoA-izomeráza genetika   metabolismus   MeSH
• EZH2 protein genetika   metabolismus   MeSH
• hepatocytární jaderný faktor 1-beta genetika   metabolismus   MeSH
• hyperplazie prostaty genetika   metabolismus   patologie   MeSH
• imunohistochemie metody   MeSH
• kohortové studie MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• metylace DNA MeSH
• mutace MeSH
• nádory prostaty genetika   metabolismus   patologie   MeSH
• prognóza MeSH
• promotorové oblasti (genetika) MeSH
• prostata patologie   MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• stupeň nádoru MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ECI2 protein, human MeSH Prohlížeč
• enoyl-CoA-izomeráza MeSH
• EZH2 protein, human MeSH Prohlížeč
• EZH2 protein MeSH
• hepatocytární jaderný faktor 1-beta MeSH
• HNF1B protein, human MeSH Prohlížeč
• messenger RNA MeSH

Epigenetic aberrations are well known to play an important role in carcinogenesis, and also have a great potential to serve as biomarkers in many types of cancers, including ovarian cancer in which sensitive and specific biomarkers and detection methods are critically needed. The aim of this study was to investigate methylation of cadherin genes CDH10, CDH13 and CDH18 in ovarian cancer tissue by comparison with control tissue. The study group consisted of 38 patients with ovarian cancer and 25 control patients. For detection of epigenetic events we used next generation sequencing, the most important data were confirmed using high-resolution melting analysis and real-time PCR. We observed significantly higher methylation in CDH13, sporadic methylation in CDH10 and loss of methylation in CDH18 in the ovarian cancer group compared with the control group. These observations suggest that changes in methylation of cadherin genes may be one of the major mechanisms associated with ovarian cancer progression. In addition, because of the high frequency of methylation of the CDH13 gene in the early stages of ovarian cancer, the analyzed CpG sites might be good targets for next study of potential ovarian cancer screening biomarkers.

• Klíčová slova
• Cadherins, Epigenetics, Methylation, Next generation sequencing, Ovarian cancer,
• MeSH
• dospělí MeSH
• kadheriny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA * MeSH
• mladý dospělý MeSH
• mucinózní adenokarcinom genetika   patologie   MeSH
• nádorové biomarkery genetika   MeSH
• nádory endometria genetika   patologie   MeSH
• nádory vaječníků genetika   patologie   MeSH
• následné studie MeSH
• prognóza MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u nádorů * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• serózní cystadenokarcinom genetika   patologie   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• H-cadherin MeSH Prohlížeč
• kadheriny MeSH
• nádorové biomarkery MeSH