Východiska: Epigenetika je vědní obor zabývající se změnami v genové expresi, které nejsou způsobeny alterací pořadí nukleotidů v řetězci DNA. Společně se sekvenčními změnami je tzv. epigenetické reprogramování jedním ze získaných znaků nádorové buňky, které řídí kancerogenezi. V rámci epigenetické regulace genové exprese se uplatňuje několik různorodých mechanizmů, z nichž nejvíce zkoumaný je proces metylace DNA. Za fyziologických podmínek zajišťuje metylace DNA řízení tkáňově specifického umlčení exprese vybraných genů a napomáhá udržovat stabilitu genomu. V procesu maligní transformace dochází ke globální hypometylaci napříč genomem a lokus specifické hypermetylaci, zejména promotorů tumor supresorových genů. Během několika posledních desítek let se ukázalo, že aberantní metylace DNA může sloužit jako biomarker nádorových onemocnění a také jako terapeutický cíl, což podnítilo probíhající snahy o vylepšení stávajících diagnostických a terapeutických možností v onkologii. Cíl: Hlavním cílem této přehledové práce je představit biomarkery asociované s nádorem a specifické testy vyvinuté pro diagnostiku nádorových onemocnění, které jsou založeny na stanovení úrovně metylace DNA. Zahrnuty jsou jak rutinně používané testy, tak nově vyvinuté komerčně dostupné testy s certifikací pro in vitro diagnostiku. Dále jsou popsány terapeutické implikace, které aberantní metylace DNA přináší, přičemž jsou zmíněna léčiva schválená i léčiva procházející klinickým hodnocením.
Background: Epigenetics is a scientific field that covers changes in gene expression that are not caused by the alteration of the nucleotide sequence in the DNA strand. Together with sequential changes, epigenetic reprogramming is a recognized cancer hallmark driving carcinogenesis. The underlying mechanisms of epigenetically-driven gene expression changes are diverse. However, one of the most extensively studied mechanisms is a change in DNA methylation. Under physiological conditions, DNA methylation ensures tissue-specific gene silencing and helps to maintain genome stability. With malignant transformation, genomic DNA undergoes global hypomethylation as well as locus-specific hypermethylation in promoters of tumor suppressor genes. In the last few decades, specific aberrant DNA methylation changes have emerged as both cancer-associated biomarkers and therapeutic targets and prompted ongoing efforts to enhance both diagnostic and therapeutic means in oncology. Purpose: The main purpose of this review is to introduce both established and emerging DNA methylation-based biomarkers for cancer diagnostics with a focus on biomarkers that are either routinely used or have been developed as commercial tests with certification for their use within in vitro diagnostics. Furthermore, therapeutic options for targeting aberrant DNA methylation are described, including both approved compounds and newly developed agents undergoing clinical investigation.
- MeSH
- časná detekce nádoru metody MeSH
- epigenomika metody MeSH
- genetické techniky klasifikace MeSH
- individualizovaná medicína metody MeSH
- lidé MeSH
- metylace DNA * fyziologie genetika MeSH
- nádorové biomarkery MeSH
- nádory * diagnóza terapie MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.
- MeSH
- cervix uteri cytologie metabolismus MeSH
- CpG ostrůvky MeSH
- epigenom MeSH
- epigenomika metody MeSH
- epitelové buňky metabolismus MeSH
- lidé MeSH
- metylace DNA * MeSH
- mutace MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádory prsu genetika metabolismus MeSH
- prognóza MeSH
- prsy cytologie metabolismus MeSH
- ROC křivka MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
- MeSH
- epigeneze genetická MeSH
- epigenomika metody MeSH
- lidé MeSH
- management nemoci MeSH
- metylace DNA * MeSH
- náchylnost k nemoci MeSH
- nádorové biomarkery * MeSH
- nádory prostaty rezistentní na kastraci krev diagnóza genetika terapie MeSH
- prognóza MeSH
- stanovení celkové genové exprese MeSH
- tekutá biopsie * metody MeSH
- výpočetní biologie metody MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
- MeSH
- editace RNA * MeSH
- epigeneze genetická * MeSH
- epigenomika metody MeSH
- lidé MeSH
- regulace genové exprese * MeSH
- transkriptom * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- úvodníky MeSH
- Geografické názvy
- Evropa MeSH
Eukaryotic mRNAs are modified by several chemical marks which have significant impacts on mRNA biology, gene expression, and cellular metabolism as well as on the survival and development of the whole organism. The most abundant and well-studied mRNA base modifications are m6A and ADAR RNA editing. Recent studies have also identified additional mRNA marks such as m6Am, m5C, m1A and Ψ and studied their roles. Each type of modification is deposited by a specific writer, many types of modification are recognized and interpreted by several different readers and some types of modifications can be removed by eraser enzymes. Several works have addressed the functional relationships between some of the modifications. In this review we provide an overview on the current status of research on the different types of mRNA modifications and about the crosstalk between different marks and its functional consequences.
Methylation systems have been conserved during the divergence of plants and animals, although they are regulated by different pathways and enzymes. However, studies on the interactions of the epigenomes among evolutionarily distant organisms are lacking. To address this, we studied the epigenetic modification and gene expression of plant chromosome fragments (~30 Mb) in a human-Arabidopsis hybrid cell line. The whole-genome bisulfite sequencing results demonstrated that recombinant Arabidopsis DNA could retain its plant CG methylation levels even without functional plant methyltransferases, indicating that plant DNA methylation states can be maintained even in a different genomic background. The differential methylation analysis showed that the Arabidopsis DNA was undermethylated in the centromeric region and repetitive elements. Several Arabidopsis genes were still expressed, whereas the expression patterns were not related to the gene function. We concluded that the plant DNA did not maintain the original plant epigenomic landscapes and was under the control of the human genome. This study showed how two diverging genomes can coexist and provided insights into epigenetic modifications and their impact on the regulation of gene expressions between plant and animal genomes.
- MeSH
- Arabidopsis genetika MeSH
- buněčné linie MeSH
- chromozomy rostlin genetika MeSH
- DNA rostlinná genetika MeSH
- epigeneze genetická genetika MeSH
- epigenom genetika MeSH
- epigenomika metody MeSH
- genom rostlinný genetika MeSH
- hybridní buňky fyziologie MeSH
- lidé MeSH
- methyltransferasy genetika MeSH
- metylace DNA genetika MeSH
- repetitivní sekvence nukleových kyselin genetika MeSH
- Check Tag
- lidé MeSH
- 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
Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
- MeSH
- analýza přežití MeSH
- anaplastická lymfomová kináza genetika metabolismus MeSH
- epigenomika metody MeSH
- gliom klasifikace genetika metabolismus MeSH
- kojenec MeSH
- lidé MeSH
- metylace DNA * MeSH
- nádory mozku klasifikace genetika metabolismus MeSH
- novorozenec MeSH
- protoonkogenní proteiny c-met genetika metabolismus MeSH
- protoonkogenní proteiny genetika metabolismus MeSH
- receptor trkA genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- sekvenování exomu metody MeSH
- tyrosinkinasové receptory genetika metabolismus MeSH
- tyrosinkinasy genetika metabolismus MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness.
- MeSH
- apoptóza genetika MeSH
- chronická lymfatická leukemie krev genetika patologie MeSH
- epigenomika metody MeSH
- lidé MeSH
- malá interferující RNA metabolismus MeSH
- metylace DNA genetika MeSH
- nádorové buňky kultivované MeSH
- nádorové supresorové proteiny genetika metabolismus MeSH
- primární buněčná kultura MeSH
- promotorové oblasti (genetika) genetika MeSH
- receptory antigenů B-buněk metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- sekvenční analýza RNA MeSH
- stanovení celkové genové exprese metody MeSH
- transkripční faktory genetika metabolismus MeSH
- upregulace MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
