Molecular genetic evidence supporting diverse histogenic origins of germ cell tumors

  • Seung‐Hyun Jung
    Department of Biochemistry, College of Medicine The Catholic University of Korea Seoul Republic of Korea
  • Hyeon‐Chun Park
    Department of Precision Medicine Research Center/IRCGP, College of Medicine The Catholic University of Korea Seoul Republic of Korea
  • Youn Jin Choi
    Department of Obstetrics/Gynecology, College of Medicine The Catholic University of Korea Seoul Republic of Korea
  • Sang Yong Song
    Department of Pathology and Translational Genomics, Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Republic of Korea
  • Yeun‐Jun Chung
    Department of Precision Medicine Research Center/IRCGP, College of Medicine The Catholic University of Korea Seoul Republic of Korea
  • Sug Hyung Lee
    Department of Biomedicine & Health Sciences, College of Medicine The Catholic University of Korea Seoul Republic of Korea

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<jats:title>Abstract</jats:title><jats:p>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‐LOH with scant CNAs. Type IV‐only GCTs are either with mitotic CN‐LOH 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 (one mature teratoma with a mucin‐secreting adenoma, two immature teratomas, and five 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 differences, which might provide important information for the identification of GCTs, especially for those with different histologic areas. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</jats:p>

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