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DOI: 10.1055/s-2008-1027406
© Georg Thieme Verlag KG Stuttgart · New York
Die Rolle epigenetischer Veränderungen in kolorektalen Karzinomen und ihren Vorläuferläsionen
Epigenetic Alterations in Colorectal Carcinomas and Precancerous LesionsPublication History
eingereicht: 4.1.2008
angenommen: 28.3.2008
Publication Date:
20 October 2008 (online)
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Zusammenfassung
Das kolorektale Karzinom stellt den dritthäufigsten malignen Tumor weltweit dar mit einer Inzidenz von 570 000 pro Jahr. Anhand der molekularen Veränderungen können (sporadische) kolorektale Karzinome in zwei unterschiedliche Phänotypen unterteilt werden. Der genetische Phänotyp, der ca. 50 – 70 % aller sporadischen kolorektalen Karzinome ausmacht, ist charakterisiert durch eine chromosomale Instabiliät (CIN) mit der klassischen Adenom-Karzinom-Sequenz, hervorgerufen durch Alterationen im APC-βCatenin-Weg mit p53-Mutationen, SMAD-Genveränderungen und LOH (loss of heterozygosity) auf 5q, 17 p 18q. Demgegenüber steht der CpG Island-Methylatorphänotyp (CIMP+), der eine epigenetische Inaktivierung von Tumorsuppressorgenen aufweist, die bei familiären Karzinomsyndromen typischerweise Keimbahnmutationen aufweisen wie z. B. Rb, VHL, hMLH1, p16 oder BRCA. Häufig gehen kolorektale Karzinome vom CIMP+-Typ mit einer Mikrosatelliteninstabilität (MSI+) einher infolge einer Promotormethylierung des Mismatch-Repair-Gens hMLH1. Weiterhin sind sie vermehrt im proximalen rechtsseitigen Kolon lokalisiert und nicht selten High-Grade-Karzinome mit muzinöser oder siegelringzelliger Differenzierung.
Abstract
Colorectal carcinomas are the third most common malignant tumours worldwide with an incidence of 570,000 per year. According to their molecular mechanisms, sporadic colorectal carcinomas can be divided into two different phenotypes. The genetic phenotype, 50 to 70 % of all sporadic colorectal carcinomas, is characterised by a chromosomal instability (CIN) with the classical adenoma-carcinoma sequence due to alteration of the APC-βcatenin pathway with p53 mutations, SMAD alterations and LOH (loss of heterozygositiy) of 5q, 17 p 18q. On the other, the CpG island methylator phenotype (CIMP+) was described with an epigenetic inactivation of tumour suppressor genes that are typically inactivated by germline mutations in familiar cancer syndromes, e. g., Rb, VHL, hMLH1, p16 or BRCA. Colorectal carcinomas of the CIMP+ type often show a high microsatellite instability (MSI+) caused by aberrant promoter methylation of the missmatch repair gene hMLH1. Further CIMP+ are located in the proximal right-side colon and show a poor grading with mucinous or signet-cell differentiation.
Schlüsselwörter
Kolorektales Karzinom - Adenom - Promotormethylierung - CIN - CIMP
Key words
colorectal carcinoma - adenoma - promotor methylation - CIN - CIMP
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Dr. Iris Tischoff
Institut für Pathologie der Ruhr-Universität Bochum an der BG Universitätsklinik Bergmannsheil
Bürkle-de-la-Camp-Platz 1
44789 Bochum
Phone: ++ 49 / 234 / 3024955
Phone: ++ 49 / 234 / 3024809
Email: iris.tischoff@rub.de