Human germ cell tumours from a developmental perspective

• Published in: Nature reviews. Cancer Vol. 19; no. 9; pp. 522 - 537
• Main Authors: Oosterhuis, J. Wolter, Looijenga, Leendert H. J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2019; Nature Publishing Group
• Subjects: 631/67/1059/2326; 631/67/1678; 631/67/1679; 631/67/1836; Alleles; Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; Cell Movement; Disease Progression; DNA damage; Embryogenesis; Embryonic Development; Embryonic growth stage; Epidemiology; Epigenesis, Genetic; Epigenetics; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Genital cancer; Genomic Imprinting; Genomics; Germ cells; Gonads; Humans; Karyotyping; Male; Medical treatment; Mutation; Neoplasms, Germ Cell and Embryonal - genetics; Neoplasms, Germ Cell and Embryonal - metabolism; Ovaries; p53 Protein; Pluripotency; Review Article; Risk factors; Stem cells; Stem Cells - metabolism; Tumors
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/s41568-019-0178-9

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. Human germ cell tumours are a heterogeneous group of neoplasms that occur in the gonads and extragonadal sites along the midline of the body. This Review outlines a developmental pathogenetic model for the origin of all germ cell tumours, which is based on the unscheduled reprogramming of cells of the early embryo and germ line.