Molecular Genetic Analysis of Bilateral Ovarian Germ Cell Tumors

Abstract

Background:

Ovarian germ cell tumors (oGCTs) are rare and highly heterogeneous with regard to their clinical and histologic appearance. The risk of tumor development is higher in children with aberrant sexual differentiation. Development of gonadoblastomas is seen in young women with 46,XY gonadal dysgenesis. At least 50 % of gonadoblastomas may develop into malignant oGCTs, mostly dysgerminomas. In this study, we evaluated bilateral oGCTs in clinically inapparent patients for sex chromosomal aberrations.

Patients and methods:

We analyzed tumor samples of 15 patients with synchronous bilateral oGCTs enrolled onto the consecutive MAKEI trials for non-testicular GCTs. Paraffin embedded samples from the Kiel German Childhood Tumor Registry were evaluated for the presence of Y-chromosomal sequences. Molecular genetic techniques included comparative genomic hybridization, polymerase chain reaction, and fluorescence in situ hybridization.

Results:

Among 15 patients with bilateral oGCTs, Y-chromosomal DNA sequences were detected in 6 tumors. Both mature teratomas were negative for Y-chromosomal DNA. Thus, 5 of 12 malignant oGCTs and 1 immature teratoma (with elevated AFP) showed Y-chromosomal material. A 45(X,0) karyotype could not be demonstrated.

Conclusions:

These investigations provide additional insight into the development of oGCTs: mature teratomas, which develop from postmeiotic germ cells, are not associated with gonadal dysgenesis. Bilateral immature teratomas, dysgerminomas and mixed malignant oGCTs may frequently show Y-chromosomal DNA, indicating underlying but clinically inapparent gonadal dysgenesis. Thus, the presence of aberrant Y-chromosomal sequences appears to be involved in tumor development in about half of these patients.

Zusammenfassung

Hintergrund:

Keimzelltumoren (KZT) des Ovars bieten ein sehr heterogenes klinisches und histologisches Bild. Eine besondere Patientengruppe stellen Mädchen mit konstitutionellen Aberrationen der Geschlechtschromosomen und der sexuellen Entwicklung dar. Junge Frauen mit einer 46,XY gonadalen Dysgenesie zeigen ein gehäuftes Auftreten von Gonadoblastomen, aus denen in 50% der Fälle maligne KZT, meist Dysgerminome, entstehen. In dieser Studie werden Tumorproben bilateraler ovarialer KZT auf Y-chromosomale DNA Sequenzen untersucht.

Patienten und Methoden:

Es wurden Tumorproben von 15 phänotypisch unauffälligen Pa­tientinnen mit bilateralen Keimzelltumoren des Ovars untersucht. Die Patienten sind Studienpatientinnen der konsekutiven MAKEI Therapieoptimierungsstudien. Die molekular­genetischen Analysen umfassten die komparative genomische Hybridisierung, Polymerasekettenreaktion und Fluoreszenz in situ Hybridisierung.

Ergebnisse:

Bei 6 der 15 Tumoren bzw. 5 von 12 Tumoren mit maligner Histologie und einem immaturen Teratom (mit erhöhtem AFP) wurde Y-chromosomale DNA nachgewiesen. Beide maturen Teratome waren negativ.

Schlussfolgerung:

Die hier vorgestellten molekulargenetischen Untersuchungen liefern weitere Einblicke in die Entstehung von ovarialen KZT. Mature Teratome, die sich von postmeio­tischen Keimzellen ableiten, scheinen nicht mit einer gonadalen Dysgenesie assoziiert. Bei der Hälfte der Patientinnen mit bilateralen immaturen Teratomen oder malignen KZT sind molekulargenetisch Hinweise auf eine zugrunde liegende, klinisch inapparente gonadale Dysge­nesie erkennbar.

Key words

ovarian germ cell tumor - dysgerminoma - gonadoblastoma - gonadal dysgenesis - Y-chromosome

Schlüsselwörter

ovariale Keimzelltumoren - Dysgerminom - Gonadoblastom - Gonadendysgenesie - Y-Chromosom

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