[Epigenetics in urothelial cancer: Pathogenesis, improving diagnostics and developing novel treatment options]. / Epigenetik des Urothelkarzinoms : Pathogenese, verbesserte Diagnostik und neue Therapieansätze.

Urothelial carcinoma of the bladder is a common tumor for which improvements in diagnostic markers and new therapy approaches, in addition to or combined with standard chemotherapy, are urgently required. Epigenetic alterations could provide both novel diagnostic markers and therapeutic targets as they are emerging as crucial factors in the development and progression of this tumor type, likely contributing to altered differentiation and metastatic potential. These alterations affect DNA methylation, histone modifications, chromatin remodeling, long noncoding RNAs, and microRNAs. Factors involved in histone modifications and chromatin remodeling appear to be particularly frequently inactivated by mutations. Thus, histone-modifying enzymes may represent good targets for rational new therapeutic approaches, although thorough investigation of their complex functions is a prerequisite. DNA methylation changes and altered miRNA expression provide promising biomarkers for diagnosis and prognosis that need further validation in comprehensive and well-standardized studies.

Major histocompatibility complex variation at class II DQA locus in the brown hare (Lepus europaeus).

The major histocompatability complex (MHC) is a multigene family of receptors that bind and present antigenic peptides to T-cells. Genes of the MHC are characterized by an outstanding genetic polymorphism, which is considered to be maintained by positive selection. Sites involved in peptide binding form binding pockets (P) that are collectively termed the peptide-binding region (PBR). In this study, we examined the level of MHC genetic diversity within and among natural populations of brown hare (Lepus europaeus) from Europe and Anatolia choosing for analysis of the second exon of the DQA locus, one of the most polymorphic class II loci. We aimed at an integrated population genetic analysis of L. europeaus by (i) correlating MHC polymorphism to genetic variability and phylogenetic status estimated previously from maternally (mtDNA) and biparentally (allozymes, microsatellites) inherited loci; and (ii) comparing full-length exon amino acid polymorphism with functional polymorphism in the PBR and the binding pockets P1, P6 and P9. A substantial level of DQA exon 2 polymorphism was detected with two completely different set of alleles between the Anatolian and European populations. However, the phylogeny of full-length exon 2 Leeu-DQA alleles did not show a strong phylogeographic signal. The presence of balancing selection was supported by a statistically significant excess of nonsynonymous substitutions over synonymous in the PBR and a trans-species pattern of evolution detected after phylogenetic reconstruction. The differentiating patterns detected between genetic and functional polymorphism, i.e. the number and the distribution of pocket variants within and among populations, indicated a hierarchical action of selection pressures.