Neues von der Adenom-Karzinom-Sequenz

Zusammenfassung

Die kolorektale Adenom-Karzinom-Sequenz (AKS) stellt den Prototyp einer Mehrschritt-Karzino­genese dar. Nachdem zunächst die formale Pa­thogenese durch Korrelation von klinischen und pathohistologischen Befunden aufgeklärt worden war, gelang es, den einzelnen Stufen dieser Sequenz (aberranter Kryptenfokus, kleines / fortgeschrittenes Adenom, Adenokarzinom) auch charakteristische molekulargenetische Aberrationen zuzuordnen: Durch Akkumulation von Tumorsuppressorgen-Verlusten (APC-Mutation als Ini­tialschritt) und Onkogen-Aktivierungen kommt es zur Entstehung von Mikrosatelliten-stabilen (MSS), aneuploiden Karzinomen; dies wird heute als „traditioneller“ oder „Chromosomaler Instabilitäts (CIN)“-Karzinogeneseweg bezeichnet, über den sich die Mehrzahl der kolorektalen Karzi­nome (KRK) entwickelt. Beim Lynch-Syndrom, dem häufigsten hereditären KRK-Syndrom, führen Keimbahnmutationen der Mismatch-Repair-Gene (MMR-Gene) zur Entwicklung diploider, Mikrosatelliten-instabiler KRK (sog. MIN- / MSI-Signalweg), die morphologisch ebenfalls der AKS folgen. Die dritte und zuletzt entdeckte „serratierte Route“ unterscheidet sich in ihren Vorläuferläsionen und molekular von den beiden anderen Pfaden. Das Konzept der Mehrschritt-Karzinogenese bildet die Rationale für die klinisch praktizierte sekundäre KRK-Prävention mittels Koloskopie-Screening und endoskopischer Entfernung der Vorläuferläsionen. Die molekularen Aberrationen (z. B. im EGFR-Signalweg) stellen Selektionskriterien für zielgerichtete Therapien dar und bieten potenzielle Ansatzpunkte für eine Primärprävention. Dieser Beitrag gibt einen Überblick über aktuelle Erkenntnisse zur sog. AKS. 

Abstract

The colorectal adenoma-carcinoma-sequence is known as the prototype of multistep carcino­genesis. After defining the formal pathogenesis through correlation of clinical and pathohistological findings, the underlying molecular aberra­tions were allocated to the individual steps of the morphological sequence (aberrant crypt foci, early / advanced adenoma, adenocarcinoma): microsatellite stable (MSS), aneuploid adenocarcinomas develop through accumulation of losses in tumor suppressor genes (with mutation / loss of the gatekeeper APC as the initiating step) and activating mutations in oncogenes; this pathway is now referred to as the traditional, chromosomal instability (CIN) pathway of colorectal carcinogenesis through which most colorectal cancers (CRC) develop. In Lynch-syndrome, the most frequent hereditary colorectal cancer syndrome, germline mutations of mismatch-repair-genes (MMR-genes) lead to the development of microsatellite instable adenocarcinomas (MIN- or MSI-pathway) which morphologically follow the adenoma-carcinoma-sequence. These cancers are ­diploid, show multiple point mutations and MSI. The third “serrated” pathway was established very recently; it develops from different precursor lesions and shows different molecular alterations. The concept of multistep carcinogenesis constitutes the rationale for secondary cancer prevention by colonoscopy screening and endoscopical removal of all precursor lesions. The molecular aberrations of CRC (e. g. in the EGFR-pathway) serve as selection criteria for targeted ther­apies and potential starting points for primary cancer prevention. This manuscript will give an overview of current new insight in the adenoma-carcinoma-sequence. 

Schlüsselwörter

Adenom-Karzinom-Sequenz - kolorektal - Karzinogenese - EGFR-Signalweg - Krebs-Prävention

Key words

adenoma - adenocarcinoma - colorectal cancer - multistep carcinogenesis - EGFR-pathway - cancer prevention

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