Biomedical subjects

M von Knebel-Doeberitz

Publications and source records attributed to M von Knebel-Doeberitz.

6 recordsLinked to original sources

PubMed2002

[Glioblastoma multiforme as a manifestation of Turcot syndrome].

Turcot's syndrome, clinically characterized by the coincident occurrence of primary tumors of the colon and the central nervous system, can genetically be divided into two syndromes: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon carcinoma (HNPCC). In the present case, a 60-year-old patient with glioblastoma multiforme and a history of hereditary malignomas is described as an example of a HNPCC-associated Turcot's syndrome. New molecular biological methods and results give deeper insight into clinical syndromes, and the better understanding improves diagnostics, therapy, and outcome estimations, even in rare diseases. In the present case, a new germinal mutation could be identified.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Optimized non-radioactive protein truncation test for mutation analysis of the adenomatous polyposis coli (APC) gene.

Germline mutations in the adenomatous polyposis coli gene cause familial adenomatous polyposis, a colon cancer predisposition syndrome. More than 95% of the identified mutations result in the generation of stop codons or reading frame shifts and encode a truncated gene product, a mutation profile also found in other tumor predisposition genes such as the breast cancer or the hereditary non-polyposis coli. Therefore the protein truncation test is ideally suited for screening of mutations in these genes, starting from simple blood samples. Gene segments of interest are amplified from genomic DNA or mRNA, thereby incorporating a T7 promoter at the 5'-end. After in vitro transcription and translation of the PCR products, the resulting protein is analysed by gel electrophoresis. Truncated translation products indicate the presence of a stop mutation. We have developed a non-radioactive protein truncation test that uses a biotinylated Lys-t-RNA to label the translation products and allows a chemiluminescent detection instead of the standard radioactive method. This generic protein truncation test kit was then used to develop a parameter-specific protein truncation test for adenomatous polyposis coli. The adenomatous polyposis coli gene was divided in 5 overlapping segments, and primers were optimized to produce distinct bands with very low background in the protein truncation test. The assay was tested on 20 familial adenomatous polyposis patient samples, where 18 mutations were found, demonstrating the efficiency of this method.

Adenomatous Polyposis Coli↗

PubMed1998

[Modification of surgical strategy in HNPCC by molecular and clinical aspects].

Because of the positive correlation between Amsterdam criteria and positive MSI analysis, a subtotal colectomy with ileorectal anastomosis seems to be indicated in patients with positive Amsterdam criteria to eliminate the high risk of metachronous colon cancer. In patients with an identified mutation in one of the known mismatch repair genes, a subtotal colectomy is indicated as well. In patients with positive Bethesda criteria, apart from the Amsterdam criteria, a subtotal colectomy seems only to be indicated if a positive MSI analysis is available.

Adult↗

PubMed1998

[Mutation localization as a guide for surgical approach in familial adenomatous polyposis?].

Restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) is considered the operative therapy of choice for the prophylactic treatment of FAP. Recently, Vasen and coworkers [5] after correlating the incidence of metachronous rectal cancer with the site of the causative APC mutation suggested subtotal colectomy and IRA to be the primary treatment in patients with mutations proximal to codon 1250, whereas IPAA should be performed in those with mutations beyond this codon. Mutation analysis in our patients after IRA, however, shows the majority of APC mutations to be located proximal to codon 1250 even in those patients with severe rectal polyposis and metachronous rectal cancer, thus not supporting the therapeutic recommendations of Vasen and coworkers.

Adenomatous Polyposis Coli↗

PubMed1997

Microsatellite instability analysis: a multicenter study for reliability and quality control.

The molecular biology section of the Hereditary Non-Polyposis Colorectal Cancer study group-Germany, instituted a multicenter study to test the reliability and quality of microsatellite instability (MSI) analysis. Eight laboratories compared MSI analyses performed on 10 matched pairs of normal and tumor DNA from patients with colorectal carcinomas. A variety of techniques were applied to the detection of microsatellite changes: (a) silver and ethidium bromide staining of polyacrylamide gels; (b) radioactive labeling; and (c) automated fluorescence detection. The identification of highly unstable tumors and tumors without MSI was achieved in high concordance. However, the interpretation of the band patterns resulted in divergent classifications at several microsatellite marker loci for a large fraction of this tumor/normal panel. The data on more than 30 primers per case suggest that the enlargement of the microsatellite panel to more than 10 loci does not influence the results. In this study, cases with MSI in less than 10% of loci were classified as microsatellite stable, whereas MSI was diagnosed in cases with more than 40% of all markers unstable. We propose that a panel of five microsatellite loci consisting of repeats with different lengths should be analyzed in an initial analysis. When less than two marker loci display shifts in the microsatellite bands from tumor DNA, the panel should be enlarged to include an additional set of five marker loci. The number of marker loci analyzed as well as the number of unstable marker loci found should always be identified. These criteria should result in reports of MSI that are more comparable between studies.

Chromosome Deletion↗

PubMed1984

No evidence for differences in the Epstein-Barr virus genome carried in Burkitt lymphoma cells and nonmalignant lymphoblastoid cells from the same patients.

Epstein-Barr virus (EBV), although not an indispensable factor for the development of Burkitt lymphoma, is apparently associated with the 20-fold higher incidence of the disease in Equatorial Africa compared to the incidence in other parts of the world. To determine whether different EBV subtypes are associated with the appearance of the malignant phenotype, we have compared the EBV genomes carried in the Burkitt tumor cells with those carried in the nonmalignant lymphoblastoid cells from the same individuals. From three patients with EBV -associated Burkitt lymphoma, tumor cell lines as well as spontaneously established lymphoblastoid cell lines representing the nonmalignant counterparts were obtained. The viral DNA in these cell lines was analyzed by Southern blot hybridization, using a set of cloned EBV DNA fragments as probes that recognize polymorphic regions in the viral genome. Using a number of different polymorphic markers to distinguish one isolate from another, the virus genome found in the tumor cells could also be identified in the nonmalignant cells of the same patient. In one case, in which two independent lymphoblastoid cell lines were established, evidence was obtained that this patient was infected by at least two distinct EBV subtypes. These results strongly suggest that in Burkitt lymphoma, the risk associated with EBV is related to cofactors such as chronic malaria and the mode of infection rather than to peculiar viral subtypes. The situation seems to be totally different from papillomavirus-associated diseases, in which the risk of progression to malignancy appears to be associated with particular viral strains.

Burkitt Lymphoma↗