The acquisition of genomic instability is one of the key characteristics of the cancer cell, and microsatellite instability (MSI) is an important segment of this phenomenon. This review aims to describe the mismatch DNA repair (MMR) system whose deficiency is responsible for MSI and discuss the cellular roles of MMR genes. Malfunctioning of the MMR repair pathway increases the mutational burden of specific cancers and is often involved in its etiology, sometimes as an influential bystander and sometimes as the main driving force. Detecting the presence of MSI has for a long time been an important part of clinical diagnostics, but has still not achieved its full potential. The MSI blueprints of specific tumors are useful for precize grading, evaluation of cancer chance and prognosis and to help us understand how and why therapy-resistant cancers arise. Furthermore, evidence indicates that MSI is an important predictive biomarker for the application of immunotherapy.

E-cadherin tumor suppressor genes are particularly active area of research in development and tumorigenesis. The calcium-dependent interactions among E-cadherin molecules are critical for the formation and maintenance of adherent junctions in areas of epithelial cell-cell contact. Loss of Ecadherin-mediated-adhesion characterises the transition from benign lesions to invasive, metastatic cancer. Nevertheless, there is evidence that E-cadherins may also play a role in the wnt signal transduction pathway, together with other key molecules involved in it, such as beta-catenins and adenomatous poliposis coli gene products.The structure and function of E-cadherin, gene and protein, in normal as well as in tumor cells are reviewed in this paper.

The association between the wnt signaling pathway and apoptosis has become more firmly established in the recent scientific literature. Many reports indicate that the wnt signaling pathway regulates apoptosis through a variety of mechanisms.The activity of wnt signaling according to specific cellular environment stimuli can either foster or restrain the processes of apoptosis. Wnt signaling regulates the early and late stages of apoptosis in both development and cellular injury in populations of neurons, endothelial cells, vascular smooth muscle cells and cardiomyocytes.In this review I draw attention to genes and proteins of the wnt signaling pathway involved in apoptosis and describe some of their functional effects.

Farming was established in Central Europe by the Linearbandkeramik culture (LBK), a well-investigated archaeological horizon, which emerged in the Carpathian Basin, in today's Hungary. However, the genetic background of the LBK genesis is yet unclear. Here we present 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic, Neolithic Starčevo and LBK sites (seventh/sixth millennia BC) from the Carpathian Basin and southeastern Europe. We detect genetic continuity of both maternal and paternal elements during the initial spread of agriculture, and confirm the substantial genetic impact of early southeastern European and Carpathian Basin farming cultures on Central European populations of the sixth-fourth millennia BC. Comprehensive Y chromosomal and mitochondrial DNA population genetic analyses demonstrate a clear affinity of the early farmers to the modern Near East and Caucasus, tracing the expansion from that region through southeastern Europe and the Carpathian Basin into Central Europe. However, our results also reveal contrasting patterns for male and female genetic diversity in the European Neolithic, suggesting a system of patrilineal descent and patrilocal residential rules among the early farmers.

Farming was established in Central Europe by the Linearbandkeramik culture (LBK), a well-investigated archaeological horizon, which emerged in the Carpathian Basin, in today’s Hungary. However, the genetic background of the LBK genesis has not been revealed yet. Here we present 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic, Neolithic Starčevo and LBK sites (7th/6th millennium BC) from the Carpathian Basin and south-eastern Europe. We detect genetic continuity of both maternal and paternal elements during the initial spread of agriculture, and confirm the substantial genetic impact of early farming south-eastern European and Carpathian Basin cultures on Central European populations of the 6th-4th millennium BC. Our comprehensive Y chromosomal and mitochondrial DNA population genetic analyses demonstrate a clear affinity of the early farmers to the modern Near East and Caucasus, tracing the expansion from that region through south-eastern Europe and the Carpathian Basin into Central Europe. Our results also reveal contrasting patterns for male and female genetic diversity in the European Neolithic, suggesting patrilineal descent system and patrilocal residential rules among the early farmers. Author Summary We report an exceptional large Neolithic DNA dataset from the Carpathian Basin, which was the cradle of the first Central European farming culture, the so called Linearbandkeramik culture. We generated 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic and Neolithic specimens from western Hungary and Croatia, attributed to the hunter-gatherers, Starčevo and LBK cultures (7th/6th millennium BC). We observe genetic discontinuity between Mesolithic foragers and early farmers, and genetic continuity between farming populations of the 6th-4th millennium BC across a vast territory of southeastern and Central Europe. Nine novel Y chromosome DNA profiles offer first insights into the Y chromosome diversity of the earliest European farmers, and further support the migration (demic diffusion) from the Near East into Central Europe along the Continental route of Neolithisation. The joint analyses of the two uniparental genetic systems let us conclude that men and women had a similar roles in the Early Neolithic migration process but their dispersal patterns were determined by sex-specific rules.

The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p = 0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p = 0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain.

Merlin, the protein product of NF2 gene, is one of the most versatile tumor suppressors capable of integrating different mechanisms that regulate cell proliferation, motility, survival and signaling pathways underlying and governing those mechanisms. Merlin is considered a member of the band 4.1 families of cytoskeleton-associated proteins also called ERM family and acts as tumor suppressor. The main cause for transformation of Schwann cells into schwannomas is credited to the inactivation of the neurofibromin 2 (NF2) gene and the consecutive loss of its protein merlin. Recent scientific advances improved our understanding of pathogenic mechanisms involving NF2 gene. The present review brings genetic properties of NF2 gene, molecular characteristics of merlin, summarizes mutational spectra and explains merlin's multifunctional roles regarding its involvement in neurofibromatosis associated tumorigenesis.

Dishevelled (DVL) proteins, three of which have been identified in humans, are highly conserved components of canonical and noncanonical Wnt signaling pathways. These multifunctional proteins, originally discovered in the fruit fly, through their different domains mediate complex signal transduction: DIX (dishevelled, axin) and PDZ (postsynaptic density 95, discs large, zonula occludens-1) domains serve for canonical beta-catenin signaling, while PDZ and DEP (dishevelled, Egl-10, pleckstrin) domains serve for non-canonical signaling. In canonical or beta-catenin signaling, DVL forms large molecular supercomplexes at the plasma membrane consisting of Wnt-Fz-LRP5/6-DVL-AXIN. This promotes the disassembly of the beta-catenin destruction machinery, beta-catenin accumulation, and consequent activation of Wnt signaling. Therefore, DVLs are considered to be key regulators that rescue cytoplasmic beta-catenin from degradation. The potential medical importance of DVLs is in both human degenerative disease and cancer. The overexpression of DVL has been shown to potentiate the activation of Wnt signaling and it is now apparent that up-regulation of DVLs is involved in several types of cancer.