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Pathogenetische Aspekte bei Vorläuferläsionen gastrointestinaler Tumoren

Pathogenetic aspects in precursor lesions of gastrointestinal tumors

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Zusammenfassung

Die Pathogenese von Vorläuferläsionen gastrointestinaler Tumoren präsentiert sich auf vielfache Weise. Im Ösophagus wird die Genexpression aberranter intestinaler Transkriptionsfaktoren wie CDX2 entscheidend durch Milieufaktoren beeinflusst. Von Dysplasien innerhalb der Barrett-Mukosa bis hin zum Adenokarzinom lassen sich in der diagnostisch einsetzbaren Vierfach-Multicolor-Fluoreszenz-in-situ-Hybridisierung (FISH) prognostische Markerkombinationen auf chromosomaler Ebene finden. In der gastralen Karzinogenesesequenz ist die Genexpression von CDX1 regulativ abhängig von der Wechselwirkung zwischen Inflammation und Promotormethylierung. Im Kolon zeigt das sessil serratierte Adenom eine Sequenz initialer BRAF-Mutation und erst spät einsetzender MLH1-Methylierung mit konsekutivem Entartungspotenzial. Parallel dazu steigt die Anzahl intraepithelialer Lymphozyten als gewohnt einfach anwendbares HE-basiertes Kriterium an. Mithilfe von Next-generation-sequencing(NGS)-Untersuchungen erstreckt sich das Spektrum an Keimbahnmutationen in Mismatchrepair-Genen als auch im APC-Gen in Bereiche geringer Penetranz, die hinsichtlich ihres Risikos stratifiziert werden sollten. Genetik, Phänotyp und Terminologie der gastrointestinalen Vorläuferläsionen verschmelzen so zu einem sich gegenseitig bedingenden Konzept innerhalb der Medizin.

Abstract

The pathogenesis of precursor lesions of gastrointestinal tumors is manifested in many ways. In the esophagus an aberrant genetic expression of intestinal transcription factors, such as CDX2 is initiated by local environment factors. During the subsequent dysplasia to carcinoma sequence, chromosomal gain and loss of genes occurs. A 4-color fluorescence in situ hybridization (FISH) assay can be applied in dysplasia as well as in Barrett’s adenocarcinoma to define prognostic marker combinations. In the gastric carcinogenesis sequence the gene expression of CDX1 is regulatively dependent on an interplay between inflammation and promotor methylation. In the colon sessile serrated adenomas show a sequence with initial BRAF mutation and late onset of MLH1 promotor hypermethylation with consecutive potential cancer progression. This event is accompanied by an increase of intraepithelial lymphocytes, which is an easy to use tool for routine diagnostics using H&E sections. Next generation sequencing (NGS) investigations of germline mutations in colorectal cancer revealed a spectrum of mutations with low penetration in the field of mismatch repair proteins as well as the APC gene. An individual risk stratification for penetration of these germline mutations is necessary. In conclusion, genetics, phenotypes and terminology of gastrointestinal precursor lesions are unified to a mutually influencing concept within medicine.

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Authors and Affiliations

  1. Pathologisches Institut, Universitätsklinikum Erlangen, Erlangen, Deutschland

    T. Rau

  2. Institut für Pathologie, Universität Bern, Murtenstr. 31, 3010, Bern, Schweiz

    T. Rau

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Rau, T. Pathogenetische Aspekte bei Vorläuferläsionen gastrointestinaler Tumoren. Pathologe 37 (Suppl 2), 186–190 (2016). https://doi.org/10.1007/s00292-016-0220-6

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  • DOI: https://doi.org/10.1007/s00292-016-0220-6

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