Search PubMed⌕ Search

Biomedical subjects

W Friedl

Publications and source records attributed to W Friedl.

At least 19 recordsLinked to original sources
PubMed2001

Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.

Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.

Adenomatous Polyposis Coli Protein↗
PubMed2001

[Hereditary colorectal carcinoma: predictive diagnosis and genetic counseling].

5 to 10 percent of colorectal cancers occur due to a genetic predisposition. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) belong to the autosomal-dominant inherited colorectal cancer syndromes. First degree relatives of affected persons are at high risk for colorectal cancer and therefore should undergo regular surveillance programs. The genetic background of FAP and HNPCC is known today, but not in every affected family the germline mutation causing the inherited disorder can be found. In some cases identification of a germline mutation is helpful to confirm a suspected diagnosis in a patient. In almost all cases it is of major importance for their family members, as it makes genetic testing and prediction of cancer risk available for persons at risk. Predictive genetic testing opens up a new dimension in relationship between patients and physicians. Test results are of great importance for future plans of a person at risk, therefore predictive genetic testing should never be performed without genetic counselling. Accordingly the German Bundesärztekammer has worked out guidelines for predictive genetic testing in hereditary tumours.

Adenomatous Polyposis Coli↗
PubMed2001

DHPLC mutation analysis of the hereditary nonpolyposis colon cancer (HNPCC) genes hMLH1 and hMSH2.

Denaturing high-performance liquid chromatography (DHPLC) is an efficient method for detection of mutations involving a single or few numbers of nucleotides, and it has been successfully used for mutation detection in disease-related genes. Colorectal cancer is one of the most common cancers, and mutations in the genes for hereditary nonpolyposis colon cancer (HNPCC), hMLH1 and hMSH2, also involve mainly point mutations. Sequence analysis is supposed to be a screening method with high sensitivity; however, it is time-consuming and expensive. We therefore decided to test sensitivity and reproducibility of DHPLC for 71 sequence variants in hMLH1 and hMSH2 initially found by sequence analysis in DNA samples of German HNPCC patients. DHPLC conditions of the PCR products were based on the melting pattern of the wild-type sequence of the corresponding PCR fragments. All but one of the 71 mutations was detected using DHPLC (sensitivity of 97%). Running time per sample averaged only 7 min, and the system is highly automated. Thus DHPLC is a rapid and sensitive method for the detection of hMLH1 and hMSH2 sequence variants.

Adaptor Proteins, Signal Transducing↗
PubMed2001

"Second hit" in sebaceous tumors from Muir-Torre patients with germline mutations in MSH2: allele loss is not the preferred mode of inactivation.

Muir-Torre syndrome is an autosomal-dominant inherited disorder predisposing to both sebaceous skin tumors and internal neoplasms. In a significant proportion of Muir-Torre syndrome patients skin tumors exhibit microsatellite instability as a hallmark of hereditary nonpolyposis colorectal cancer. Most individuals predisposed to hereditary nonpolyposis colorectal cancer harbor a germline mutation in the DNA mismatch repair genes MSH2 or MLH1. In Muir-Torre syndrome the vast majority of germline mutations have been identified in MSH2. Microsatellite instability in tumor tissue develops after somatic inactivation of the corresponding second mismatch repair allele ("second hit"). So far, the mechanisms of somatic inactivation of the second allele in microsatellite instability positive tumors from patients with known mismatch repair germline mutations are not well understood. We examined whether allele loss (loss of heterozygosity) is a frequent mechanism for inactivation of the second MSH2 allele in a sample of nine microsatellite instability positive skin tumors from eight unrelated Muir-Torre patients with known MSH2 germline mutations. Loss of heterozygosity was determined using microsatellite markers or heteroduplex analysis, respectively. Only one of the nine skin tumors exhibited loss of heterozygosity at the MSH2 locus. Thus, we could show in a sample of sebaceous tumors from patients with genetically proven Muir-Torre syndrome that loss of heterozygosity most probably is not the preferred mode of somatic inactivation of the second MSH2 allele.

Adult↗
PubMed2001

Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families.

BACKGROUND AND AIMS: In familial adenomatous polyposis (FAP), correlations between site of mutation in the adenomatous polyposis coli (APC) gene and severity of colonic polyposis or extracolonic manifestations are well known. While mutation analysis is important for predictive diagnosis in persons at risk, its relevance for clinical management of individual patients is open to question. METHODS: We examined 680 unrelated FAP families for germline mutations in the APC gene. Clinical information was obtained from 1256 patients. RESULTS: APC mutations were detected in 48% (327/680) of families. Age at diagnosis of FAP based on bowel symptoms and age at diagnosis of colorectal cancer in untreated patients were used as indicators of the severity of the natural course of the disease. A germline mutation was detected in 230 of 404 patients who were diagnosed after onset of bowel symptoms (rectal bleeding, abdominal pain, diarrhoea). When these patients were grouped according to the different sites of mutations, mean values for age at onset of disease differed significantly: patients carrying APC mutations at codon 1309 showed a disease onset 10 years earlier (mean age 20 years) compared with patients with mutations between codons 168 and 1580 (except codon 1309) (mean age 30 years), whereas patients with mutations at the 5' end of codon 168 or the 3' end of codon 1580 were diagnosed at a mean age of 52 years. Within each group of patients however large phenotypic variation was observed, even among patients with identical germline mutations. A higher incidence of desmoids was found in patients with mutations between codons 1445 and 1580 compared with mutations at other sites, while no correlation between site of mutation and presence of duodenal adenomas was observed. CONCLUSIONS: As age at manifestation and course of the disease may be rather variable, even in carriers of identical germline mutations, therapeutic decisions should be based on colonoscopic findings in individual patients rather than on the site of mutation. However, in patients with mutations within codons 1445-1580, it may be advisable to postpone elective colectomy because desmoids may arise through surgical intervention.

Adenomatous Polyposis Coli↗
PubMed2001

Detection of APC and k-ras mutations in the serum of patients with colorectal cancer.

Detection of tumor DNA in peripheral blood of patients with colorectal cancer (CRC) may allow early diagnosis of tumor disease and be of prognostic value. However, a reliable tumor marker detectable in the serum of patients with this disease is missing. Because k-ras and APC mutations occur frequently and at an early stage in CRCs, these mutations might also be detected in the serum of CRC patients and serve as tumor markers. Hence, tumor tissues of CRC patients were examined for the presence of mutations in the k-ras and APC genes. If a mutation was detected in the tumor, the serum of the patient was screened subsequently for the presence of this mutation. K-ray mutations were detected in 22 of 30 colorectal tumor tissues, but only in six patients was the mutation identified in their serum samples. Mutations of the APC gene were identified in 25 of 65 tumors: 20 of these 25 patients showed the respective mutation in their serum. Given their higher detection rate, APC mutations could be a more informative serum marker than k-ras in CRC patients.

Adenocarcinoma↗
PubMed2000

Mapping of a gene for nonspecific X-linked mental retardation (MRX 75) to Xq24-q26.

Nonspecific X-linked mental retardation is a heterogeneous condition consisting of nonsyndromal mental retardation in males. It is caused by mutation in one of several genes on the X chromosome (MRX genes). Here we report on the localization of a presumptive MRX gene to chromosomal region Xq24-q26 in a German family with nonspecific X-linked mental retardation (MRX 75, HUGO Human Gene Nomenclature Committee). Two point linkage analysis with 23 informative markers gave a lod score of 2.53 at theta = 0 for markers DXS425, DXS1254, DXS1114, and HPRT.

Genetic Linkage↗
PubMed2000

ADULT syndrome allelic to limb mammary syndrome (LMS)?

In 1993, we described an autosomal-dominant syndrome in a German family characterized by ectrodactyly/syndactyly, dysplasia of nails, lacrimal duct atresia, hypodontia, hypoplastic breasts and nipples, intensive freckling (ADULT syndrome, acro-dermato-ungual-lacrimal-tooth syndrome, MIM 103285). In 1996 a large Dutch family with an autosomal-dominant syndrome ("limb mammary syndrome", LMS, MIM *603543) characterized by hypoplasia/aplasia of mammary glands and nipples, ectrodactyly, other hand/foot anomalies, lacrimal-duct atresia, nail dysplasia, hypohidrosis, cleft palate/bifid uvula, hypodontia was reported. In this family the disease locus was recently mapped to the chromosomal region 3q27 through a genome-wide linkage screen. Given the similarity of manifestations we hypothesized that the two syndromes might be allelic. We genotyped 21 members of the ADULT family with 19 polymorphic markers from the chromosomal region 3q27 and obtained a maximal lod score of 4.82 at straight theta = 0.00 with marker D3S1288. Our results place the ADULT locus to the same chromosomal region where LMS was mapped, suggesting that these two conditions are allelic.

Abnormalities, Multiple↗
PubMed2000

[Calcaneus pseudarthrosis: a clinical rarity].

The calcaneus pseudoathrosis is rarely seen in clinical workday and we couldn't find any case be reported. In two cases the authors present the diagnosis and therapy of a non-union after a calcaneus fracture. The authors point especially at anatomical characteristics and biomechanical reasons and their meaning for aetiology of pseudoathrosis after a calcaneus fracture.

Adolescent↗
PubMed2000

Interstitial deletion in Xp22.3 is associated with X linked ichthyosis, mental retardation, and epilepsy.

We describe monozygotic male twins with an interstitial deletion of Xp22.3 including the steroid sulphatase gene (STS). The twins had X linked ichthyosis, X linked mental retardation, and epilepsy. A locus for X linked mental retardation has been assigned to a region between STS and DXS31 spanning approximately 3 Mb. Recently the locus was further refined to an approximately 1 Mb region between DXS1060 and GS1. By PCR analysis of flanking STS gene markers in our patients we succeeded in narrowing down the locus to between DXS6837 and GS1.

Arylsulfatases↗
PubMed2000

Approaches to identification of HNPCC suspected patients in Slovak population.

Patients with hereditary non-polyposis colorectal cancer (HNPCC) have a DNA mismatch repair defect (MMR) in their tumor tissue that results in instability of microsatellite DNA sequences (MSI). Thus, MSI analysis may effectively indicate this form of cancer that should be then proved by analysis of germline mutations in MMR genes. The aim of this study was to identify HNPCC suspected patients in the Slovak population by investigating microsatellite instability in colorectal tumor tissues. MSI was studied at 5-11 loci in matched tumor and normal DNA using radioactively labeled PCR products separated on sequencing gels. High microsatellite instability (MSI-H) was present only in patients younger than 50 years, in 100% of patients having two affected relatives by colorectal cancer and in 67% of patients with only one affected relative. In both groups of patients colorectal cancer was present in two successive generations. No MSI-H was found in the group of patients older than 50 years, even if they had positive family history for colorectal cancer. Among all markers used, the BAT26 mononucleotide repeat (100%), DI0S197 and D13S175 (62.5%) dinucleotide repeats were the most frequently altered in the tumor tissues. Retrospective analysis revealed that some of the patients having MSI-H tumors have had clinicopathological characteristics frequently reported to HNPCC. The family members of those patients with MSI-H are enrolled in preventive health care program until mutational analyses will enable to select carriers from non-carriers of mutated MMR genes.

Adult↗
PubMed1999

Peutz-Jeghers syndrome: four novel inactivating germline mutations in the STK11 gene. Mutations in brief no. 227. Online.

The diagnosis of Peutz-Jeghers syndrome is based on the occurrence of hamartomatous gastrointestinal polyps and perioral pigment spots. In view of the development of hamartomatous polyps in several syndromes and the variability of pigment spots in Peutz-Jeghers patients, identification of affected individuals is difficult. Recently, germline mutations in the STK11 gene have been reported as a molecular cause of Peutz-Jeghers syndrome. We present four novel inactivating mutations identified by direct sequencing of all 9 exons of the STK11 gene in 4 patients suggestive of Peutz-Jeghers syndrome: three frameshift mutations (125-137del; 474-480del; 516-517insT) and one nonsense mutation (Q220X). Our data obtained in these patients and in those reported previously emphasize the diagnostic value of histological discrimination between different types of hamartomatous polyps and of molecular analysis, particularly in cases with no family history of the disease.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

[In Process Citation]

To optimise the microsurgical training in our clinic we organized a permanent possibility to practice microsurgical techniques of vascular anastomosis. This includes step-wise education by means of plastic materials, human placenta and the rat model. The most important role in this concept is played by the placenta. It supplies a realistic simulation of different in vivo situations concerning microvascular anastomosis. As to availability, handling and costs the placenta is superior to animal models and has replaced them almost completely in our educational concept.

Journal Article↗