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Musil Z.,Institute of Biology and Medical Genetics | Duskova J.,Charles University | Burton D.,Warren Grant Magnuson Clinical Center | Merino M.J.,U.S. National Institutes of Health | And 2 more authors.
European Journal of Clinical Investigation | Year: 2011

Background Pheochromocytomas are tumours arising from chromaffin tissue located in the adrenal medulla associated with typical symptoms and signs which may occasionally develop metastases, which are defined as the presence of tumour cells at sites where these cells are not found. This retrospective analysis was focused on clinical, genetic and histopathologic characteristics of primary metastatic versus primary benign pheochromocytomas. Materials and methods We identified 41 subjects with metastatic pheochromocytoma and 108 subjects with apparently benign pheochromocytoma. We assessed dimension and biochemical profile of the primary tumour, age at presentation and time to develop metastases. Results Subjects with metastatic pheochromocytoma presented at a significantly younger age (41·4±14·7 vs. 50·2±13·7years; P<0·001) with larger primary tumours (8·38±3·27 vs. 6·18±2·75cm; P<0·001) and secreted more frequently norepinephrine (95·1% vs. 83·3%; P=0·046) compared to subjects with apparently benign pheochromocytomas. No significant differences were found in the incidence of genetic mutations in both groups of subjects (25·7% in the metastatic group and 14·7% in the benign group; P=0·13). From available histopathologic markers of potential malignancy, only necrosis occurred more frequently in subjects with metastatic pheochromocytoma (27·6% vs. 0%; P<0·001). The median time to develop metastases was 3·6years with the longest interval 24years. Conclusions In conclusion, regardless of a genetic background, the size of a primary pheochromocytoma and age of its first presentation are two independent risk factors associated with the development of metastatic disease. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation. No claim to original US government works.

Frynta D.,Charles University | Palupcikova K.,Charles University | Bellinvia E.,Charles University | Benda P.,Charles University | And 4 more authors.
Zootaxa | Year: 2010

Spiny mice belonging to the cahirinus-dimidiatus group of the genus Acomys have become a widely used model in physiology and behaviour. To improve current knowledge concerning the phylogeny of this taxon, we analysed 24 samples from Libya, Chad, Egypt, Jordan, Cyprus, Crete, Turkey, Yemen and Iran. We sequenced the whole mitochondrial control region and part of the flanking tRNA genes for a total length of 986 to 996 bp and described 22 haplotypes. Our results confirmed that the Afro-Mediterranean and Asian clades are clearly distinct (p-distance = 6-8.1%). The former clade corresponds to A. cahirinus sensu lato (i.e. including also the Cretan A. minous, Cypriot A. nesiotes and Turkish A. cilicicus). Haplotypes of A. cahirinus from the E Sahara (S Egypt, SW Libya, N Chad) grouped with those of A. cilicicus and A. minous (p-distance ≤ 2.2%), while haplotypes of A. nesiotes grouped with one haplotype representing the commensal A. cahirinus from Cairo (p-distance = 1.2%). Close similarity among haplotypes from mainland Africa and NE Mediterranean (clade A. cahirinus sensu stricto) support the hypothesis that ancestors of A. nesiotes, A. cilicicus and A. minous dispersed most probably as commensal populations, thus questioning their status of valid species. The most surprising finding was the considerable genetic variation in Asia. In addition to a haplogroup from Sinai and Jordan (corresponding to A. dimidiatus sensu stricto), we detected two previously unknown haplogroups, from Yemen and Iran + United Arab Emirates. These clades are fairly distinct and separate species/subspecies status of these animals might be further considered. Copyright © 2010.

Soukupova J.,Charles University | Pohlreich P.,Charles University | Seemanova E.,Institute of Biology and Medical Genetics
NeuroMolecular Medicine | Year: 2011

Ataxia telangiectasia (AT) is a genomic instability syndrome characterised, among others, by progressive cerebellar degeneration, oculocutaneous telangiectases, immunodeficiency, elevated serum alpha-phetoprotein level, chromosomal breakage, hypersensitivity toionising radiation and increased cancer risk. This autosomal recessive disorder is caused by mutations in the ataxia telangiectasia mutated (ATM) gene coding for serine/threonine protein kinase with a crucial role in response to DNA double-strand breaks. We characterised genotype and phenotype of 12 Slavic AT patients from 11 families. Mutation analysis included sequencing of the entire coding sequence, adjacent intron regions, 3′UTR and 5′UTR of the ATM gene and multiplex ligation-dependent probe amplification (MLPA) for the detection of large deletions/duplications at the ATM locus. The high incidence of new and individual mutations demonstrates a marked mutational heterogeneity of AT in the Czech Republic. Our data indicate that sequence analysis of the entire coding region of ATM is sufficient for a high detection rate of mutations in ATM and that MLPA analysis for the detection of deletions/duplications seems to be redundant in the Slavic population. © Springer Science+Business Media, LLC 2011.

Schanze D.,University Hospital Magdeburg | Neubauer D.,University Hospital Magdeburg | Cormier-Daire V.,University of Paris Descartes | Delrue M.-A.,Pellegrin Hospital | And 15 more authors.
Human Mutation | Year: 2014

Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner. © 2014 WILEY PERIODICALS, INC.

Slyskova J.,Academy of Sciences of the Czech Republic | Slyskova J.,Institute of Biology and Medical Genetics | Korenkova V.,Academy of Sciences of the Czech Republic | Collins A.R.,University of Oslo | And 18 more authors.
Clinical Cancer Research | Year: 2012

Purpose: DNA repair capacity (DRC) is a determinant not only of cancer development but also of individual response to therapy. Previously, altered base and nucleotide excision repair (BER and NER) have been described in lymphocytes of patients with sporadic colorectal cancer. We, for the first time, evaluate both excision repair capacities in human colon biopsies to study their participation in colorectal tumorigenesis. Experimental design: Seventy pairs of tumor and adjacent healthy tissues were analyzed for BER- and NER-specificDRCby a comet repair assay. Tissue pairs were further compared for expression levels of a panel of 25 BER and NER genes complemented by their promoter methylation status. Results: We observed a moderate increase of NER-DRC (P = 0.019), but not of BER-DRC in tumors. There was a strong correlation between both tissues for all investigated parameters (P < 0.001). However, 4 NER (CSB, CCNH, XPA, XPD) and 4 BER (NEIL1, APEX1, OGG1, PARP1) genes showed a 1.08- to 1.28-fold change difference in expression in tumors (P < 0.05). Individual gene expression levels did not correlate with overall DRC, and we did not detect any aberrant methylation of the investigated genes. Conclusions: Our complex analysis showed that tumor cells are not deficient in BER and NER, but rather follow patterns characteristic for each individual and are comparable with adjacent tissue. Alteration of excision repair pathways is not a pronounced event in colorectal carcinogenesis. This study shows the feasibility of DRC evaluation in human solid tissues, representing a complex marker of multigene DNA repair processes. ©2012 AACR.

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