Chromosomes and expression in human testicular germ-cell tumors: insight into their cell of origin and pathogenesis

Abstract

Human germ-cell tumors (GCTs) are a heterogeneous group of neoplasms. Based on epidemiology, anatomical site of presentation, histology, chromosomal constitution, and pattern of genomic imprinting, GCTs are classified into five entities. Within the testis, three types of GCTs can be diagnosed: type I (teratomas and yolk-sac tumors of neonates and infants); type II (seminomas and nonseminomas); type III (spermatocytic seminomas). Here the focus is on the type II GCTs, the most frequent type in the adult testis (so-called TGCTs). They can also be diagnosed in dysgenetic gonads (an incomplete or defective formation of the gonad, caused by a disturbed process of migration of the germ cells and/or their correct organization in their fetal gonadal ridge), the anterior mediastinum, and pineal/suprasellar region. In the testis, they originate from the malignant counterpart of primordial germ cells/gonocytes, referred to as carcinoma in situ (CIS)/intratubular germ-cell neoplasia unclassified (ITGCNU). CIS/ITGCNU and seminomatous cells are characterized by expression of OCT3/4 and NANOG, while in addition embryonal carcinoma expresses SOX2, all identified as transcription factors related to pluripotency in embryonic stem (ES) cells. With the exception of teratomas, most histological elements of TGCTs are sensitive for (cisplatin-based) chemotherapy; CIS/ITGCNU and seminoma cells are also sensitive to DNA damage induced by irradiation. Similar observations have been made for ES cells and their derivates. Moreover, the genetic constitution of TGCTs (low incidence of mutations and frequent uniparental disomies) can also be linked to characteristics of ES cells, likely related to their specific inability to repair DNA damage and their high sensitivity to apoptotic cell death. The unusual presence of wild-type P53 in TGCTs is explained by specific expression of a cluster of micro-RNAs (miRNAs), that is, hsa-miR 371-373, also expressed in ES cells, which prevents P53-driven cellular senescence upon oncogenic stress. Many characteristics of human TGCTs reflect the nonmalignant counterparts from which they originate. Demonstration of these characteristics, in combination with the knowledge of the abnormal niche of these cells, normally occupied by spermatogonia, allows an informative method for (early) diagnosis. The conclusion is that TGCTs are embryonic cancers found in adults.