Gonadoblastoma risk in women with dysgenetic gonads
Most patients with dysgenetic gonads have a 45,X/46,XY chromosome picture in their blood cells suggesting the dysfunction of some genes on the X and Y chromosomes expressed in gonad or germ cells of the early embryo. This view gains support from the fact that a gonadal tumor composed of germ cells and gonad derivatives called “Gonadoblastoma” is found almost exclusively (96%) in the dysgenetic gonads of 46,XY individuals. These so called germ line tumors (gonadoblastoma, dysgerminoma, seminoma) are described in the literature to occur with a risk of at least 30% in this patient group. In the clinic, these patients are therefore usually advised a complete removal of their gonad before puberty.
However, the question is raised whether the mere presence of the Y chromosome is sufficient for this high gonadoblastoma risk, or whether it is more likely that only the “expression dose” of one or more Y genes mapped to the GBY locus and expressed in fetal gonads and germ cells is responsible for the development of tumor cells in the dysgenetic gonad later on ?
Within the german research network “Disorders of Sex Development (DSD)” centered in Lübeck and granted by the BMBF (Bundesministerium für Bildung und Forschung), we now have established a clinical diagnostic center between the unit of “Paediatric Endocrinology and Diabetes” of the children’s clinic and our molecular diagnostic laboratory for analysis of the molecular etiology of tumor cell development in all patients (males or females) with dysgenetic gonads.
What happens during the GBY study ?
Patients interested in taking part in this study are asked to contact us directly by phone or letter or e-mail, or via their doctors for getting more detailed informations about the benefits and personal risks of this molecular genetic approach aimed to reveal the real personal risk for gonadal tumor development. After informed consent has been obtained the network coordinators will provide the doctors with a comprehensive questionnaire including a clinical anamnesis protocol and a complete endocrinological diagnostic scheme. Blood samples (25 ml EDTA blood) will then be collected from every patient and sent to Heidelberg for DNA and RNA extraction together with a completed GBY-genes-questionnaire.
The doctor will also indicate the appropriateness and consent of the patient to have a gonadal tissue biopsy performed for analysing its inherent tumor risk. Gonadal tissue samples fixed and embedded in paraffin blocks from each patient for identification of the precise tissue pathology are first evaluated from the collaborating clinical center including an analysis of putative neoplastic cells and their classification as gonadoblastoma or dysgerminoma cells (right and left gonad sample are recommended for separate diagnosis).
The rest of the patient´s gonad tissue, i.e., not needed for fixed paraffin sections, is collected in a special cryo-tube and snap-frozen immediately after surgical removing on dry ice or plunged in liquid nitrogen. The frozen tissue samples are sent directly to Heidelberg in a dry ice box. All data are centrally and anonymously collected in the existing clinical network database.
The blood sample of the patients is also needed for analysing the potential benefit of blood cells in diagnosing the expression quality of the GBY genes and their X homologues in this easily accessible cell type. Comparison of their expression profiles in blood cells and gonad cells will reveal whether it might be possible to prognose the patient´s risk for gonadal tumor cells already from blood cells in future.
Benefits/risks
The examination does not involve any risks beyond the standard clinical diagnostic programme. The costs of the GBY gene expression diagnosis are taken over by the collaborating research centers. Of course, the genetic material extracted from the blood cells or tissue (DNA or RNA) is not used to carry out any other kind of genetic analysis.
A direct benefit for the patient would be that this study might diagnose a lower gonadal tumor risk than given before and that the general recommendation of removal the complete gonads in case of dysgenesis and Y chromosome can be omitted.