Molecular genetic evidence supporting diverse histogenic origins of germ cell tumors.

Germ cell tumors (GCTs) originate during the histogenesis of primordial germ cells to mature gametes. Previous studies identified five histogenic mechanisms in ovarian mature teratomas (type I: failure of meiosis I, type II: failure of meiosis II, type III: duplication of the genome of a mature gamete, type IV: no meiosis, and type V: fusion of two different ova), but those of other GCTs remain elusive. In this study, we analyzed 84 GCTs of various pathologic types to identify the histogenesis using single-nucleotide polymorphism array by analyzing copy-neutral loss-of-heterozygosity (CN-LOH) and copy number alterations (CNAs). We detected types I and II in ovarian teratomas, type III in ovarian teratomas and yolk sac tumors (YSTs), and type IV in all GCT types. The GCTs with multiple type histogenesis (I-IV) (ovarian mature/immature teratomas and YST) show meiotic CN-LOHs with scant CNAs. Type IV-only GCTs are either with mitotic CN-LOHs and abundant CNAs (seminoma, dysgerminoma, testicular mixed GCTs) or with scant CNAs and no CN-LOH (pediatric testicular and mediastinal teratomas). The development sequences of CN-LOH and CNA are different between the multiple type (I-IV) GCTs and type IV-only GCTs. We analyzed two different histologic areas in eight GCTs (1 mature teratoma with a mucin-secreting adenoma, 2 immature teratomas, and 5 mixed GCTs). We found that GCTs (mature teratoma, immature teratoma and mixed GCT) showed different genomic alterations between histologic areas, suggesting that genomic differences within a GCT could accompany histologic differentiation. Of note, we found evidence for collision tumors in a mixed GCT. Our data indicate that GCTs may have various histogenesis and intratumoral genomic difference, which might provide important information for the identification of GCTs, especially for those with different histologic areas. This article is protected by copyright. All rights reserved.