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Klinik und Genetik des familiären Darmkrebses

Clinical findings and genetics of familial colorectal cancer

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medizinische genetik

Zusammenfassung

Eine familiäre Häufung von Dickdarmkrebs (CRC) und ein früher Erkrankungsbeginn sind Hinweise auf erbliche Tumorsyndrome, die für etwa 3–5% aller CRC verantwortlich sind. Bei diesen monogenen Dispositionen wird der erbliche Dickdarmkrebs ohne Polyposis (HNPCC/Lynch-Syndrom) von der Gruppe der gastrointestinalen Polyposis-Syndrome unterschieden. Bei vielen hereditären Formen besteht ein z. T. charakteristisches Spektrum extrakolonischer Tumoren. Die frühe Erkennung und korrekte Einordnung ist wichtig, da effektive Methoden der Vorsorge und Therapie für Betroffene und Risikopersonen bestehen.

Die Initialdiagnostik umfasst das endoskopische Bild und den histologischen Befund, ergänzt um extraintestinale Manifestationen und die Familienanamnese. Die molekulargenetische Abklärung erfolgt nach weitgehend etablierten und standardisierten Algorithmen. Differenzialdiagnostische Probleme bereiten insbesondere Patienten mit wenigen kolorektalen Adenomen sowie phänotypische Überlappungen bei hamartomatösen Polyposis-Syndromen. Für HNPCC und häufige Polyposis-Syndrome existieren etablierte risikoadaptierte Früherkennungsprogramme.

Der außerhalb der etablierten Tumorsyndrome beobachteten familiären Häufung des – oft spätmanifesten – CRC und dem Auftreten weniger Adenome liegt vermutlich eine multifaktorielle Ätiologie zugrunde. Die Aufklärung der genetischen Faktoren und das Verständnis der beteiligten Signalwege steht hier noch am Anfang, macht aber durch die rasanten methodischen Entwicklungen (z. B. genomweite Assoziationsstudien, CNV-Analysen) rasche Fortschritte.

Abstract

Familial clustering of colorectal cancer (CRC) and early disease onset are indicators of an inherited tumour syndrome. Monogenic dispositions account for 3–5% of all CRC cases and are subdivided into hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome) and various gastrointestinal polyposis syndromes. Many of these syndromes are characterised by a broad spectrum of extracolonic tumours. Early detection and accurate classification are essential in providing effective surveillance and treatment.

Initial diagnosis is based on endoscopic and histological findings as well as on the presence of extracolonic manifestations and family history. Molecular genetic examination is important for the differential diagnosis, evaluation of recurrence risk, and predictive testing of asymptomatic at risk individuals; it is performed according to largely standardised algorithms. Diagnostic difficulties are common among the hamartomatous polyposes due to their broad phenotypic overlap and frequent uncertainties in histological evaluation, as well as among patients with few adenomas. Risk-adapted surveillance guidelines have been established for HNPCC and for the more frequently observed polyposis syndromes.

Beyond established tumour syndromes, familial clustering of CRC (which is often of late onset) or the occurrence of few adenomas is likely to be based upon a multifactorial (complex) etiology. Although identification of the underlying genetic risk factors and biological pathways is still in the early stages, rapid progress is being made due to methodical developments such as genome-wide association studies and CNV analysis.

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Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht. Die Autoren werden von der Deutschen Krebshilfe e. V. gefördert.

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  1. Institut für Humangenetik, Universitätsklinikum Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Deutschland

    V. Steinke, S. Vogt &  S. Aretz

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  2. S. Vogt
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Correspondence to S. Aretz.

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Steinke, V., Vogt, S. & Aretz, S. Klinik und Genetik des familiären Darmkrebses. medgen 22, 265–281 (2010). https://doi.org/10.1007/s11825-010-0226-z

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