Human germ cell tumours from a developmental perspective

J. Wolter Oosterhuis, Leendert H.J. Looijenga

Research output: Contribution to journalReview articlepeer-review

155 Citations (Scopus)

Abstract

Human germ cell tumours (GCTs) are derived from stem cells of the early embryo and the germ line. They occur in the gonads (ovaries and testes) and also in extragonadal sites, where migrating primordial germ cells are located during embryogenesis. This group of heterogeneous neoplasms is unique in that their developmental potential is in effect determined by the latent potency state of their cells of origin, which are reprogrammed to omnipotent, totipotent or pluripotent stem cells. Seven GCT types, defined according to their developmental potential, have been identified, each with distinct epidemiological and (epi)genomic features. Heritable predisposition factors affecting the cells of origin and their niches likely explain bilateral, multiple and familial occurrences of the different types of GCTs. Unlike most other tumour types, GCTs are rarely caused by somatic driver mutations, but arise through failure to control the latent developmental potential of their cells of origin, resulting in their reprogramming. Consistent with their non-mutational origin, even the malignant tumours of the group are characterized by wild-type TP53 and high sensitivity for DNA damage. However, tumour progression and the rare occurrence of treatment resistance are driven by embryonic epigenetic state, specific (sub)chromosomal imbalances and somatic mutations. Thus, recent progress in understanding GCT biology supports a comprehensive developmental pathogenetic model for the origin of all GCTs, and provides new biomarkers, as well as potential targets for treatment of resistant disease.

Original languageEnglish
Pages (from-to)522-537
Number of pages16
JournalNature Reviews Cancer
Volume19
Issue number9
DOIs
Publication statusPublished - 1 Sept 2019

Keywords

  • Alleles
  • Animals
  • Biomarkers, Tumor/genetics
  • Cell Movement
  • Disease Progression
  • Embryonic Development
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Neoplastic
  • Genomic Imprinting
  • Genomics
  • Humans
  • Karyotyping
  • Male
  • Mutation
  • Neoplasms, Germ Cell and Embryonal/genetics
  • Stem Cells/metabolism

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