Aspekte der Molekularen Pathogenese des Zervixkarzinoms für neue Marker in der Krebsfrüherkennung und Diagnostik

Zusammenfassung

Die Mortalitätsraten des Zervixkarzinoms konnten durch die Einführung eines bevölkerungsweiten Screenings von Frauen mit Hilfe des sog. Pap-Tests drastisch gesenkt werden. Dennoch sind diese Untersuchungen mit einer hohen Rate falsch-positiver und falsch-negativer Testergebnisse behaftet, so daß technische Verbesserungen der bisher üblichen Screeninguntersuchungen dringend erforderlich sind. Sogenannte „high risk”-Typen der humanen Papillomviren (HR-HPVs) sind als die kausalen Agentien des Zervixkarzinoms erkannt worden. Der Nachweis dieser Virusinfektionen erlaubt es, prinzipiell gefährdete Frauen zu erfassen, dennoch kommen diese Infektionen bei etwa 5-30 % der weiblichen Bevölkerung vor und nur ein sehr kleiner Prozentsatz der Infizierten entwickelt eine klinisch relevante Läsion. Durch Aktivität zweier viraler Onkogene, E6 und E7, können einige wenige HR-HPV-infizierte Zellen in einem sehr langwierigen Prozeß nach und nach in Krebszellen umfunktioniert werden. In der Folge der Aktivität des viralen E7-Onkogens wird ein zelluläres Markerprotein (p16) in den dysplastischen Zellen deutlich verstärkt exprimiert. Mit Hilfe hochspezifischer Antikörper können daher unabhängig vom jeweiligen HR-HPV-Typ Zervixdysplasien und daraus abgeleitete Karzinome sowohl in der Histologie wie auch der Zytologie eindeutig nachgewiesen werden (CINtec-Verfahren). In weit fortgeschrittenen dysplastischen Läsionen kommt es oft zur Integration des HR-HPV-Genoms in das Genom der Wirtszelle. Dies ist mit der verstärkten Expression der viralen Onkogene verbundenen. Durch den Nachweis viraler mRNA-Moleküle, die von den integrierten viralen Genomen abgeschrieben werden, konnte ein Marker für besonders progressionsgefährdete Krebsvorstufen entwickelt werden (APOT-Verfahren). Auf der Basis dieser neuen Marker werden daher absehbar sehr sensitive, stabile, einfache und somit auch sehr kostengünstige Krebsvorsorgemaßnahmen entwickelt werden können.

Aspects of the molecular pathogenesis of cervical cancer to define new markers for cancer early detection and diagnosis

Summary

The mortality rates of cervical cancer could be drastically reduced by the implementation of population wide cytological screening test for women (Pap-Test). However, these screening tests are hampered by high rates of false positive and false negative results, pointing to the urgent demand for improved screening technologies. High risk human papillomaviruses were identified as the causal agents of cervical cancer. The detection of the viral infection allows to identify patients at risk, however, about 5-30 % of the normal female population harbours these viruses and only very few of these develop clinically relevant lesions. The activity of two viral oncogenes E6 and E7 initiates in a long term process neoplastic transformation in few of the HPV harbouring cells. As consequence of the expression of E7 a cellular marker protein (p16) is increasingly expressed in dysplastic cells. Monoclonal antibodies directed against p16 allow therefore to specifically identify dysplastic cells and derived invasive cancers in histological slides but also cytological smears (CINtec Assay). In advanced preneoplastic lesions HPV genomes are often integrated into cellular chromosomes. This leads to enhanced expression of the viral oncogenes. The detection of specific viral mRNA transcripts derived from integrated HPV genomes allows to identify preneoplastic lesions with a particularly high risk for progression to invasive cancers (APOT-assay). These findings will allow to establish highly sensitive, but specific and cost efficient new cancer early detection assays.

Schlüsselwörter

Zervixkarzinom - Dysplasie - Pathogenese - molekular - p16 - APOT

Key words

Cervical cancer - pathogenesis - molecular - dysplasia - p16 - APOT

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