ESPE Abstracts (2018) 89 S2.1

The Biology of Germ Cell Tumors in Disorders of Sex Development

Leendert Looijenga


Erasmus Medical Center, Rotterdam, Netherlands


Germ cell tumors (GCTs) comprise a heterogeneous group of neoplasms. The WHO classification 2016 recognizes three types of testicular GCTs, including the GCNIS-related (Germ Cell Neoplasia In Situ) GCTs, being the malignant seminomas and nonseminomas. They originate from a totipotent embryonic germ cell. GCNIS, seminoma and embryonal carcinoma, are characterized by the pluripotency marker OCT3/4 (POU5F1). Seminomas (and GCNIS) are positive for SOX17 and embryonal carcinomas for SOX2. Individuals with part of the Y chromosome (GBY) are at higher risk, likely related to TSPY. This directly relates to risk stratification of individual patients with various types of Disorders of Sex Development (DSD). Detection of KITLG (SCF) is informative for the earliest phase of GCNIS formation. A new level of risk stratification has been provided based on Genome Wide Association studies (GWAS) indicating that a selection of Single Nucleotide Polymorphisms (SNPs) are associated with testicular GCTs. These map to a limited number of genes related to relevant pathways, including gonadal development (DMRT1), embryonic germ cell proliferation and maintenance (KITLG, SPRY4, TERT, BAK1, etc). Data will be presented that this information is informative in a clinical context. A unifying model will be presented in which a delicate interaction between the genomic constitution and (gonadal) micro-environment (GENVIRONMENT) is the actual determinant for the risk of an individual to develop a malignant testicular GCT, including patients with DSD. Functional studies on the role of P53 identified that a selected set of embryonic-specific microRNAs, being the miRs 371-3 and 302/367 clusters are highly expressed in the various types of GCTs, including the precursor lesion GCNIS. The only exception is the fully differentiated element teratoma. These miR are informative as molecular serum markers to identify patients with a malignant GCT at the moment of diagnosis, as well as during clinical follow up. The current data based on a quantitative detection protocol will be presented, showing the outperformance of this test compared to the currently used standard biomarkers AFP and hCG.

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