Abstract
BackgroundOvarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia.ResultsWe examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2γ) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13–40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH.ConclusionThis study provides new data supporting two distinct but overlapping pathways in OGCT development; one involving spontaneous KIT mutation(s) leading to increased survival and proliferation of undifferentiated oogonia, the other related to presence of Y chromosome material and ensuing gonadal dysgenesis in phenotypic females.
Highlights
Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood
Immunohistochemistry pattern of expression in OGCTs and foetal ovaries The expression pattern in OGCTs of a panel of markers for testicular GCTs is summarised in Table 1 and illustrated in Fig. 1 and 2
Expression of the stem cell-related markers OCT-3/4 and KIT were present in 80% of dysgerminomas, 75–100% of tumours containing gonadoblastoma and in two yolk sac tumours, whereas NANOG and AP-2γ were present in approximately half of the dysgerminomas and gonadoblastomas
Summary
Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia. Malignant ovarian (OGCTs) have a median age at onset of 18 years and represent approximately 3% of all ovarian cancers in Western countries [1]. The following histological subtypes exist: dysgerminoma, yolk sac tumour, embryonal carcinoma, polyembryoma, choriocarcinoma, immature teratoma, and mixed GCTs. Bilateral tumours occur in up to 10% of cases [1,2]. The fact that OGCTs often affect women in their reproductive years further imply the importance of optimal therapy in order to maximize the number of women in which ovarian function can be conserved
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