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  • 1
    Abstract: 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.
    Type of Publication: Journal article published
    PubMed ID: 9354434
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  • 2
    ISSN: 1432-2307
    Keywords: Colorectal carcinoma ; Hereditary non-polyposis colonic cancer ; Microsatellite instability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Very recently a new molecular mechanism in the tumorigenesis of colorectal carcinoma has been described which is closely linked to hereditary non-polyposis colonic cancer (HNPCC). Ubiquitous changes in the length of simple repetitive DNA sequences between constitutional and tumour DNA occur in about 90% of cases of HNPCC and in about 15% of cases of non-familial, sporadic colorectal carcinoma. Such microsatellite instabilities have been shown to be the phenotypical marker of mutations in the human homologues of prokaryotic mismatch repair genes (MutS, MutL, MutH). These data provide crucial new tools in the detection of patients at high risk of developing colon cancer and other HNPCC-related carcinomas. In addition, these developments provide new insights into a new, presumably primary event in oncogenesis, i.e. the occurrence of mutations in genomic stability genes leading to an increased cellular mutation rate (“mutator phenotype”) and thus to cancer.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-2307
    Keywords: Colon cancer ; Hereditary non-polyposis colon cancer ; Microsatellite ; Polymerase chain reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of the present study was to establish a rapid, non-radioactive screening method for the detection of microsatellite instability (MIN). MIN is the primary characteristic of the mutator phenotype in tumours constituting hereditary non-polyposis colon cancers (HNPCC). We investigated 30 patients suffering from colorectal cancer using a non-radioactive PCR-based technique. MIN was present in 7 of 30 (23%) of the cases. There was a statistically significant correlation between MIN and localization of the tumour. Five of 7 (72%) tumours with MIN but only 4 of 23 (17%) tumours without MIN were localized in the proximal colon (P〈0.01). There was a tendency to higher MIN frequency in tumours of patients with familial clustering of cancers. However, this was statistically not significant (P〉0.05). In addition, no correlation between MIN and tumour grade and stage was found. For the investigations in the present study we used a non-radioactive PCR-based method followed by denaturating polyacrylamide gel electrophoresis and silver staining. This method is highly sensitive and reproducible. Thus, PCR-based analysis using a non-radioactive staining technique represents a comprehensive tool for MIN screening in diagnostic pathology.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1600-0536
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1468-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Three cases of solitary circumscribed neuroma (so-called palisaded, encapsulated neuroma) arising in the dermis have been studied. Two patients were male and one was female, with ages ranging from 27 to 59 years. All lesions arose on the forehead. Histologically, the neoplasms were partly encapsulated and were composed of broad fascicles, nests, and whorl-like structures of bland appearing spindle cells often separated by artefactual clefts. Immunohistochemically. most of the tumour cells stained positive for S-100 protein, and a considerable number also for CD 34, but failed to stain for epithelial membrane antigen and melanoma associated antigens. Solitary circumscribed neuroma has to be distinguished from long-standing dermal melanocytic nevus, mucosal neuromas seen in type lib multiple endocrine neoplasia (MEN) syndrome, classical and cellular schwannoma, neurofibroma. perineurioma, traumatic neuroma, and angioleiomyoma.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Carbohydrate Research 230 (1992), S. 245-256 
    ISSN: 0008-6215
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0138-4988
    Keywords: Life Sciences ; Life Sciences (general)
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Process Engineering, Biotechnology, Nutrition Technology
    Notes: In a prospective study, nuclear DNA was extracted from colorectal tumours and normal mucosa which had been fixed in buffered formalin and embedded into paraffin. DNA-extraction was performed using three different methods: a commercial kit which was not especially created for this use; a known fast procedure without DNA-cleaning steps; and a more conventional DNA-preparation protocol with DNA-cleaning. Using the polymerase chain reaction (PCR), DNA was amplified by being targeted onto two β-globin fragments with different lengths (536 bp and 989 bp) and (CA)n repeats localized on chromosome 5q (D5S346) and chromosome 17p (TP53CA) with a length of about 100 bp for detection of microsatellite instability. The success rate of microsatellite amplification was 100% with all methods. The 536 bp β-globin fragment could be amplified with a success rate ranging from 40% to 100%. The amplification of the 989 bp β-globin fragment was unsuccessful. Significant differences were observed between the three methods in the final DNA concentration and DNA yield. In microsatellite instability studies of paraffin-embedded tissues, the investigator can expect a high success rate of nearly 100% using any of the described methods.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1963
    Keywords: Schlüsselwörter Hereditäres nonpolypöses kolorektales Karzinom HNPCC) ; Molekulares Screening ; Tumorphänotyp ; Mikrosatelliteninstabilität ; Mismatch-Repairgene ; Key words Hereditary non-polyposis colorectal cancer (HNPCC) ; Molecular screening ; Tumor phenotype ; Microsatellite instability ; Mismatch repair genes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary During the last few years, the molecular basis of several cancer predisposition syndromes has been discovered which offers new tools for cancer prevention and early detection. This will be demonstrated in one of the most frequent hereditary cancer syndromes, namely the hereditary nonpolyposis colorectal cancer (HNPCC) which accounts for about 5% to 8% of CRC. Thereby, families with exclusively CRC (Lynch type I syndrome) and those with extracolonic cancers especially of endometrium, stomach, small bowel and upper urinary tract (Lynch type II syndrome) can be discriminated. At the molecular level, HNPCC is caused by germline mutations in one of the mismatch repair genes (hMSH2, hMLH1, hMSH6, hPMS2). Thus, nucleotide mispairings occurring particularly within simple repetitive genomic sequences (microsatellites) during replication are no longer be repaired properly and can be demonstrated by PCR as so-called microsatellite instability (MSI). Since more than 90% of HNPCC associated and only about 15% of sporadic CRC show MSI, this test is a useful tool for HNPCC screening. In case of a negative result HNPCC is highly unlikely. In positive cases (with ≥2 out of 5 unstable defined microsatellite markers) the definite molecular diagnosis can only be obtained by sequencing the mismatch repair genes from the patient’s blood or normal DNA. As immunohisto-chemistry reveals loss of hMSH2 or hMLH1 expression in most MSI positive CRC, these data provide useful information for the sequencing strategy. Molecular tumor screening by MSI test and immunohistochemistry is recommended in patients i.) with a positive family history (acc. to the Amsterdam criteria), ii.) suffering from multiple HNPCC related carcinomas, iii.) with HNPCC related cancer before 45ys of age, and iv.) with right-sided CRC exhibiting medullary, signet-ring or mucinous differentiation. Finally, these tests as well as genetic counseling and treatment of the patient need to be done by an interdisciplinary approach. Thereby, the pathologist can substantially contribute to identify HNPCC related carcinomas either by clinical or morphological criteria and to initiate the molecular screening test.
    Notes: Zusammenfassung Die Aufklärung der molekularen Grundlagen einer Reihe erblicher Krebsdispositionssyndrome eröffnet bislang nicht gekannte Möglichkeiten der Krebsprävention und Krebsfrühdiagnostik. Dies wird am Beispiel eines der häufigsten erblichen Krebssyndrome, dem hereditären nichtpolypösen kolorektalen Karzinom (HNPCC), aufgezeigt, welches etwa 5–8% aller kolorektalen Karzinome (CRC) ausmacht und autosomal dominant vererbt wird. Dabei wird zwischen Familien mit ausschließlich CRC (Lynch-I-Syndrom) und Familien unterschieden, bei denen auch extrakolische Tumoren auftreten, insbesondere des Endometriums, Magens, Dünndarms und der oberen ableitenden Harnwege (Lynch-II-Syndrom). Molekulare Ursachen des HNPCC-Syndroms sind Keimbahnmutationen in einem der sog. Mismatch-Repairgene (hMSH2, hMLH1, hMSH6, hPMS2). Als Folge dieser Genmutation werden bei der Zellteilung insbesondere in einfach repetitiven DNA-Sequenzen (Mikrosatelliten) auftretende Nukleotid-Fehlpaarungen (Mismatches) nicht mehr repariert. Solche Mismatches lassen sich mittels PCR als Mikrosatelliten-Instabilität (MSI) nachweisen. Da etwa 90% aller HNPCC-assoziierten und nur 15% der sporadischen CRC MSI positiv sind, bietet sich die Mikrosatelliten-Analyse als Screeningmethode auf HNPCC an. Verglichen wird jeweils DNA von Normal- und Tumorgewebe desselben Patienten mit mindestens 5 definierten Mikrosatelliten Markern. Bei negativem Testergebnis ist ein HNPCC-Syndrom unwahrscheinlich; bei positivem Testergebnis (≥2 der 5 Marker instabil) ist zum molekularen Beweis einer vererbten Keimbahnmutation die Sequenzierung des Mismatch-Repairgene im Blut oder Normalgewebe erforderlich. Der immunhistochemische Nachweis eines Verlustes der Expression von hMSH2 oder hMLH1 kann für die Wahl des zuerst zu sequenzierenden Gens herangezogen werden. Ein molekulares Tumorscreening (MSI Test und Immunhistochemie) sollte bei Risikopatienten durchgeführt werden, d.h. bei Patienten mit 1. positiver Familienanamnese (nach sog. Amsterdam-Kriterien), 2. Mehrfachtumoren aus dem HNPCC-Tumorspektrum, 3. HNPCC assoziiertem Tumor vor dem 45. Lebensjahr und bei 4. rechtsseitigem CRC mit geringer (solid-kribriformer, medullärer oder siegelringzelliger) oder muzinöser Differenzierung. Insgesamt stellen diese Untersuchungen einschließlich der weiteren Familienberatung eine interdisziplinäre Herausforderung dar. Dabei kann der Pathologe bereits anhand der klinischen und tumorpathologischen Befunde einen bedeutenden Beitrag zur Identifikation von HNPCC Risikopatienten leisten.
    Type of Medium: Electronic Resource
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