Translationale Forschung in der gynäkologischen Onkologie: Serum-Tumormarker zur Früherkennung des Ovarialkarzinoms

Zusammenfassung

Bedingt durch Chemotherapieresistenz und das Fehlen einer Methode zur Früherkennung besitzt das Ovarialkarzinom die ungünstigste Prognose unter den gynäkologischen Malignomen. Um die Mortalität zu senken, gilt es, eine geeignete Methode zur Früherkennung zu etablieren, die wegen der geringen Inzidenz des Ovarialkarzinoms eine Spezifität von über 99 % und einen positiven Prädiktionswert von mindestens 10 % aufweisen muss. Da bildgebende Verfahren sich als ungeeignet erwiesen haben, könnten neue Serummarker des Ovarialkarzinoms – etwa in Ergänzung zum etablierten Tumormarker CA-125 – als Früherkennungsmarker dienen. In den letzten Jahren wurde mit molekularen Screeningmethoden und anspruchsvoller Biostatistik eine Vielzahl neuer Marker identifiziert. Verschiedene Markerkombinationen sind auf ihre Wertigkeit zur Erkennung von Frühstadien bereits untersucht worden, andere werden in internationalen Studien derzeit evaluiert. Die vorliegende Übersichtsarbeit gibt zum einen einen Überblick über den Stand der Forschung und stellt zum anderen ein eigenes translationales Projekt in den Kontext der aktuellen Literatur. Mit Oligonukleotidarray-Analysen wurden Kandidatengene identifiziert, deren Expression im Karzinom hoch und im Normalgewebe niedrig ist. Durch einen eigens entwickelten Algorithmus wurden verschiedene ins Blut sezernierbare Gene eruiert. Vier dieser Gene (Osteopontin [OPN], Secretory Leukoprotease Inhibitor [SLPI], Kallikrein 10 [KLK10] und Matrix-Metalloproteinase-7 [MMP-7]) sowie CA-125 wurden mit ELISA-Analysen im Serum von 67 Ovarialkarzinompatientinnen und von 130 gesunden Frauen untersucht. Verschiedene Markerkombinationen konnten die Karzinom-Seren mit 96 – 98,7 %iger Sensitivität und 99,7 – 100 %iger Spezifität identifizieren. Auch alle Karzinom-Frühstadien (n = 9) konnten von den Normalseren abgegrenzt werden. Eine prospektive Studie mit einer hohen Fallzahl von Frühstadien des Ovarialkarzinoms und unter Einbeziehung weiterer Biomarker erscheint notwendig, um die Ergebnisse zu validieren.

Abstract

Ovarian cancer carries the worst prognosis among all gynaecological cancers, mainly due to the chemoresistance and the lack of an effective screening method for the detection of early stage disease. Early detection will be necessary to reduce the mortality of ovarian cancer. Since it has a low incidence, any screening method has to exhibit a specificity of 99 % and a positive predictive value of 10 %. Imaging techniques including transvaginal ultrasound evaluation have not reached this aim and, therefore, novel biomarkers in addition to the well established CA-125 may serve as early detection markers. Molecular screening methods with biostatistic evaluation have identified many novel biomarkers. Several marker panels have been evaluated so far, others are under investigation. This review summarizes the research status and presents also our translational project with regard to the actual literature. Utilizing oligonucleotide arrays, we identified candidate genes with high expression in cancer tissues as compared to normal controls. After developing an algorithm to identify secreted proteins, we found several genes, of which four (osteopontin, secretory leukoprotease inhibitor, kallikrein 10 and matrix metalloproteinase-7) together with CA-125 were evaluated in serum samples of 67 ovarian cancer patients and 130 healthy women. Different marker combinations could distinguish cancer from normal serum with 96 – 98.7 % sensitivity and 99.7 – 100 % specificity, respectively. In addition, all early stage cancer cases (n = 9) could be identified. A prospective study including a high number of early stage ovarian cancers and using additional novel biomarkers is warranted to validate the results.

Schlüsselwörter

Screening - Tumormarker - Markerpanel - Ovarialkarzinom - Früherkennung

Key words

screening - biomarker - panel - ovarian cancer - early detection

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