Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Human germ cell tumours from a developmental perspective

Nature Reviews Cancer volume 19, pages 522–537 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Developmental potency states of cells of the early embryo and primordial germ cells.
Fig. 2: Developmental origin of germ cell tumours.
Fig. 3: Extragonadal human germ cell tumours at sites of mismigrated primordial germ cells.

Similar content being viewed by others

References

  1. Wang, Z. et al. Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor. Nat. Genet. 49, 1141–1147 (2017). The first and so far only study applying next-generation sequencing, single nucleotide polymorphism arrays and expression arrays to intracranial GCTs; the results allow comparison of type I and type II GCTs.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Trabert, B., Chen, J., Devesa, S. S., Bray, F. & McGlynn, K. A. International patterns and trends in testicular cancer incidence, overall and by histologic subtype, 1973-2007. Andrology 3, 4–12 (2015).

    CAS  PubMed  Google Scholar 

  3. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J. Clin. Oncol. 15, 594-603 (1997).

  4. Oosterhuis, J. W. & Looijenga, L. H. Testicular germ-cell tumours in a broader perspective. Nat. Rev. Cancer 5, 210–222 (2005).

    CAS  PubMed  Google Scholar 

  5. Oosterhuis, J. W., Looijenga L. H. J. in Pathology and Biology of Human Germ Cell Tumors. (ed Jimenez R. E. Nogales F. F.) Ch. 3, 23–129 (Springer, 2017).

  6. Hackett, J. A. & Surani, M. A. Regulatory principles of pluripotency: from the ground state up. Cell Stem Cell 15, 416–430 (2014). This article discusses the plasticity of pluripotency states of ESCs and how they can be manipulated; it forms the basis for the classification of GCTs proposed in this Review.

    CAS  PubMed  Google Scholar 

  7. Smith, A. Formative pluripotency: the executive phase in a developmental continuum. Development 144, 365–373 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Macfarlan, T. S. et al. Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature 487, 57–63 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Yamaji, M. et al. Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat. Genet. 40, 1016–1022 (2008).

    CAS  PubMed  Google Scholar 

  10. Ohinata, Y. et al. Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436, 207–213 (2005).

    CAS  PubMed  Google Scholar 

  11. Weber, S. et al. Critical function of AP-2 gamma/TCFAP2C in mouse embryonic germ cell maintenance. Biol. Reprod. 82, 214–223 (2010).

    CAS  PubMed  Google Scholar 

  12. Irie, N. et al. SOX17 is a critical specifier of human primordial germ cell fate. Cell 160, 253–268 (2015). A fundamental study into the factors specifying and maintaining human PGCs, especially related to the switch from SOX2 to SOX17 in the context of the transition of ESCs to PGCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kojima, Y. et al. Evolutionarily distinctive transcriptional and signaling programs drive human germ cell lineage specification from pluripotent stem cells. Cell Stem Cell 21, 517–532.e515, (2017). This article establishes the collaboration between SOX17, TFAP2C and BLIMP1 in the specification of the germ line in humans.

    CAS  PubMed  Google Scholar 

  14. Kobayashi, T. & Surani, M. A. On the origin of the human germline. Development 145, dev150433 (2018).

    PubMed  Google Scholar 

  15. Spencer, R. Parasitic conjoined twins: external, internal (fetuses in fetu and teratomas), and detached (acardiacs). Clin. Anat. 14, 428–444 (2001). A comprehensive review of parasitic and included twins, convincingly showing the continuum between monozygotic twins, conjoined twins, parasitic twins and included twins (type 0 GCTs), and type I GCTs.

    CAS  PubMed  Google Scholar 

  16. Prescher, L. M. et al. Fetus in fetu: review of the literature over the past 15 years. J. Pediatr. Surg. Case Rep. 3, 554–562 (2015).

    Google Scholar 

  17. Abbott, T. M., Hermann, W. J., Jr. & Scully, R. E. Ovarian fetiform teratoma (homunculus) in a 9-year-old girl. Int. J. Gynecol. Pathol. 2, 392–402 (1984).

    CAS  PubMed  Google Scholar 

  18. Cornejo, K. M., Cheng, L., Church, A., Wang, M. & Jiang, Z. Chromosome 12p abnormalities and IMP3 expression in prepubertal pure testicular teratomas. Hum. Pathol. 49, 54–60 (2016).

    CAS  PubMed  Google Scholar 

  19. Emerson, R. E. et al. Evidence of a dual histogenetic pathway of sacrococcygeal teratomas. Histopathology 70, 290–300 (2017).

    PubMed  Google Scholar 

  20. Yanai-Inbar, I. & Scully, R. E. Relation of ovarian dermoid cysts and immature teratomas: an analysis of 350 cases of immature teratoma and 10 cases of dermoid cyst with microscopic foci of immature tissue. Int. J. Gynecol. Pathol. 6, 203–212 (1987).

    CAS  PubMed  Google Scholar 

  21. Mikuz, G. et al. Therapy-resistant metastasizing anaplastic spermatocytic seminoma: a cytogenetic hybrid: a case report. Anal. Quant. Cytopathol. Histpathol. 36, 177–182 (2014).

    PubMed  Google Scholar 

  22. Wagner, T., Grantham, M. & Berney, D. Metastatic spermatocytic tumour with hybrid genetics: breaking the rules in germ cell tumours. Pathology 50, 562–565 (2018).

    PubMed  Google Scholar 

  23. van Gurp, R. J., Oosterhuis, J. W., Kalscheuer, V., Mariman, E. C. & Looijenga, L. H. Biallelic expression of the H19 and IGF2 genes in human testicular germ cell tumors. J. Natl Cancer Inst. 86, 1070–1075 (1994).

    PubMed  Google Scholar 

  24. Schneider, D. T. et al. Multipoint imprinting analysis indicates a common precursor cell for gonadal and nongonadal pediatric germ cell tumors. Cancer Res. 61, 7268–7276 (2001).

    CAS  PubMed  Google Scholar 

  25. Sievers, S. et al. IGF2/H19 imprinting analysis of human germ cell tumors (GCTs) using the methylation-sensitive single-nucleotide primer extension method reflects the origin of GCTs in different stages of primordial germ cell development. Genes Chromosomes Cancer 44, 256–264 (2005).

    CAS  PubMed  Google Scholar 

  26. Stier, S. et al. Loss of imprinting of the insulin-like growth factor 2 and the H19 gene in testicular seminomas detected by real-time PCR approach. Arch. Toxicol. 80, 713–718 (2006).

    CAS  PubMed  Google Scholar 

  27. Looijenga, L. H. et al. Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene. Cancer Res. 66, 290–302 (2006).

    CAS  PubMed  Google Scholar 

  28. Killian, J. K. et al. Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors. Genome Res. 26, 1490–1504 (2016). A comprehensive study of the epigenome of testicular type II GCTs showing that their stem cells and differentiated derivatives retain the epigenomic features of their normal counterparts.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Giannoulatou, E. et al. Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline. PLoS ONE 12, e0178169 (2017).

    PubMed  PubMed Central  Google Scholar 

  30. Fukushima, S. et al. Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas. Acta Neuropathol. 133, 445–462 (2017).

    CAS  PubMed  Google Scholar 

  31. Zhang, C., Berney, D. M., Hirsch, M. S., Cheng, L. & Ulbright, T. M. Evidence supporting the existence of benign teratomas of the postpubertal testis: a clinical, histopathologic, and molecular genetic analysis of 25 cases. Am. J. Surg. Pathol. 37, 827–835 (2013).

    PubMed  Google Scholar 

  32. David, S. et al. More cases of benign testicular teratomas are detected in adults than in children. A clinicopathological study of 543 testicular germ cell tumor cases. Pathol. Oncol. Res. 23, 513–517 (2017).

    CAS  PubMed  Google Scholar 

  33. Honecker, F. et al. ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up. Ann. Oncol. 29, 1658–1686 (2018).

    CAS  PubMed  Google Scholar 

  34. de Jong, J. et al. Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications. J. Pathol. 215, 21–30 (2008).

    PubMed  Google Scholar 

  35. Stoop, H. et al. Reactivity of germ cell maturation stage-specific markers in spermatocytic seminoma: diagnostic and etiological implications. Lab. Invest. 81, 919–928 (2001).

    CAS  PubMed  Google Scholar 

  36. Rajpert-De Meyts, E. et al. The immunohistochemical expression pattern of Chk2, p53, p19INK4d, MAGE-A4 and other selected antigens provides new evidence for the premeiotic origin of spermatocytic seminoma. Histopathology 42, 217–226 (2003).

    CAS  PubMed  Google Scholar 

  37. Lim, J. et al. OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia. J. Pathol. 224, 473–483 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Mamsen, L. S., Brochner, C. B., Byskov, A. G. & Mollgard, K. The migration and loss of human primordial germ stem cells from the hind gut epithelium towards the gonadal ridge. Int. J. Dev. Biol. 56, 771–778 (2012). An elegant morphological study of migration of PGCs in the human embryo, showing that mismigrated PGCs are localized where extragonadal GCTs may develop.

    CAS  PubMed  Google Scholar 

  39. Gonzalez-Crussi, F. Extragonadal Teratomas. Vol. 18 (Armed Forces Institute of Pathology, 1982).

  40. Bowles, J. & Koopman, P. Retinoic acid, meiosis and germ cell fate in mammals. Development 134, 3401–3411 (2007).

    CAS  PubMed  Google Scholar 

  41. Williamson, S. R. in Pathology of the Mediastinum (ed A. M. Marchevsky) 146–168 (Cambridge University Press 2014).

  42. Ahmad, R. et al. Functional neuronal cells generated by human parthenogenetic stem cells. PLoS ONE 7, e42800 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. McLaren, A. Germ cells and germ cell sex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 350, 229–233 (1995).

    CAS  PubMed  Google Scholar 

  44. Upadhyay, S. & Zamboni, L. Ectopic germ cells: natural model for the study of germ cell sexual differentiation. Proc. Natl Acad. Sci. USA 79, 6584–6588 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Adams, I. R. & McLaren, A. Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis. Development 129, 1155–1164 (2002).

    CAS  PubMed  Google Scholar 

  46. Teilum, G. Special Tumors of Ovary and Testis and Related Extragonadal Lesions: Comparative Pathology and Histological Identification (Munksgaard, 1976).

  47. Oosterhuis, J. W., Stoop, H., Honecker, F. & Looijenga, L. H. Why human extragonadal germ cell tumours occur in the midline of the body: old concepts, new perspectives. Int. J. Androl. 30, 256–263 (2007).

    PubMed  Google Scholar 

  48. De Backer, A. et al. Influence of tumor site and histology on long-term survival in 193 children with extracranial germ cell tumors. Eur. J. Pediatr. Surg. 18, 1–6 (2008).

    PubMed  Google Scholar 

  49. Hoei-Hansen, C. E. et al. New evidence for the origin of intracranial germ cell tumours from primordial germ cells: expression of pluripotency and cell differentiation markers. J. Pathol. 209, 25–33 (2006).

    CAS  PubMed  Google Scholar 

  50. Bartkova, J. et al. Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: implications for the anti-tumor barrier concept and treatment. Mol. Oncol. 8, 1667–1678 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Runyan, C., Gu, Y., Shoemaker, A., Looijenga, L. & Wylie, C. The distribution and behavior of extragonadal primordial germ cells in Bax mutant mice suggest a novel origin for sacrococcygeal germ cell tumors. Int. J. Dev. Biol. 52, 333–344 (2008).

    CAS  PubMed  Google Scholar 

  52. Stampfer, M. R. & Yaswen, P. Human epithelial cell immortalization as a step in carcinogenesis. Cancer Lett. 194, 199–208 (2003).

    CAS  PubMed  Google Scholar 

  53. Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–179 (1996).

    CAS  PubMed  Google Scholar 

  54. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  55. Flores, I. & Blasco, M. A. The role of telomeres and telomerase in stem cell aging. FEBS Lett. 584, 3826–3830 (2010).

    CAS  PubMed  Google Scholar 

  56. Szablewski, L. Expression of glucose transporters in cancers. Biochim. Biophys. Acta. 1835, 164–169 (2013).

    CAS  PubMed  Google Scholar 

  57. Sainz de la Maza, D. et al. Metabolic reprogramming, autophagy, and reactive oxygen species are necessary for primordial germ cell reprogramming into pluripotency. Oxid. Med. Cell Longev. 2017, 4745252 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Richardson, B. E. & Lehmann, R. Mechanisms guiding primordial germ cell migration: strategies from different organisms. Nat. Rev. Mol. Cell Biol. 11, 37–49 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Isaacs, H., Jr. Perinatal (fetal and neonatal) germ cell tumors. J. Pediatr. Surg. 39, 1003–1013 (2004).

    PubMed  Google Scholar 

  60. Scott, L. The origin of monozygotic twinning. Reprod. Biomed. Online 5, 276–284 (2002).

    PubMed  Google Scholar 

  61. Hall, J. G. Twinning. Lancet 362, 735–743 (2003).

    PubMed  Google Scholar 

  62. Machin, G. Familial monozygotic twinning: a report of seven pedigrees. Am J. Med. Genet. C. Semin. Med. Genet. 151C, 152–154 (2009).

    PubMed  Google Scholar 

  63. Kaku, H., Usui, H., Qu, J. & Shozu, M. Mature cystic teratomas arise from meiotic oocytes, but not from pre-meiotic oogonia. Genes Chromosomes Cancer 55, 355–364 (2016). This study demonstrates that type IV GCTs are derived from meiotic oocytes, and proposes that escape from meiotic arrest is a key factor in their pathogenesis.

    CAS  PubMed  Google Scholar 

  64. Miura, K. et al. Methylation imprinting of H19 and SNRPN genes in human benign ovarian teratomas. Am. J. Hum. Genet. 65, 1359–1367 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Surti, U., Hoffner, L., Chakravarti, A. & Ferrell, R. E. Genetics and biology of human ovarian teratomas. I. Cytogenetic analysis and mechanism of origin. Am. J. Hum. Genet. 47, 635–643 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang, M. et al. Estradiol promotes and maintains cumulus cell expression of natriuretic peptide receptor 2 (NPR2) and meiotic arrest in mouse oocytes in vitro. Endocrinology 152, 4377–4385 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Comerci, J. T., Jr., Licciardi, F., Bergh, P. A., Gregori, C. & Breen, J. L. Mature cystic teratoma: a clinicopathologic evaluation of 517 cases and review of the literature. Obstet. Gynecol. 84, 22–28 (1994).

    PubMed  Google Scholar 

  68. Huddart, R. A. et al. Familial predisposition to both male and female germ cell tumours? J. Med. Genet. 33, 86 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Gobbi, D., Fascetti Leon, F., Aquino, A., Melchionda, F. & Lima, M. Metachronous bilateral ovarian teratoma: a germ-line familial disorder and review of surgical management options. J. Pediatr. Adolesc. Gynecol. 26, e105–e107 (2013).

    CAS  PubMed  Google Scholar 

  70. Sanchez, F. & Smitz, J. Molecular control of oogenesis. Biochim. Biophys. Acta 1822, 1896–1912 (2012).

    CAS  PubMed  Google Scholar 

  71. Hui, P. in World Health Organization Classification of Tumours of Female Reproductive Organs (ed R. J. Kurman) 163–166 (IARC Press, 2014).

  72. Conti, M., Hsieh, M., Zamah, A. M. & Oh, J. S. Novel signaling mechanisms in the ovary during oocyte maturation and ovulation. Mol. Cell. Endocrinol. 356, 65–73 (2012).

    CAS  PubMed  Google Scholar 

  73. Dumesic, D. A., Meldrum, D. R., Katz-Jaffe, M. G., Krisher, R. L. & Schoolcraft, W. B. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil. Steril. 103, 303–316 (2015).

    PubMed  Google Scholar 

  74. Murdoch, S. et al. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat. Genet. 38, 300–302 (2006).

    CAS  PubMed  Google Scholar 

  75. Parry, D. A. et al. Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte. Am. J. Hum. Genet. 89, 451–458 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Gross-Thebing, T. et al. The vertebrate protein dead end maintains primordial germ cell fate by inhibiting somatic differentiation. Dev. Cell 43, 704–715.e705 (2017). An elegant study in zebrafish demonstrating the key role of Dnd in protecting and maintaining PGC fate.

    CAS  PubMed  Google Scholar 

  77. Dawson, E. P. et al. Delayed male germ cell sex-specification permits transition into embryonal carcinoma cells with features of primed pluripotency. Development 145, dev156612 (2018).

    PubMed  PubMed Central  Google Scholar 

  78. Honecker, F. et al. Pathobiological implications of the expression of markers of testicular carcinoma in situ by fetal germ cells. J. Pathol. 203, 849–857 (2004).

    CAS  PubMed  Google Scholar 

  79. Stoop, H. et al. Differentiation and development of human female germ cells during prenatal gonadogenesis: an immunohistochemical study. Hum. Reprod. 20, 1466–1476 (2005).

    CAS  PubMed  Google Scholar 

  80. Cairns, L. A. et al. Kit regulatory elements required for expression in developing hematopoietic and germ cell lineages. Blood 102, 3954–3962 (2003).

    CAS  PubMed  Google Scholar 

  81. Runyan, C. et al. Steel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration. Development 133, 4861–4869 (2006).

    CAS  PubMed  Google Scholar 

  82. Nettersheim, D. et al. BMP inhibition in seminomas initiates acquisition of pluripotency via NODAL signaling resulting in reprogramming to an embryonal carcinoma. PLoS Genet. 11, e1005415 (2015). This study demonstrates in vitro reprogramming of a seminoma cell to an EC cell by BMP inhibition.

    PubMed  PubMed Central  Google Scholar 

  83. Nettersheim, D. et al. SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate. Oncotarget 7, 47095–47110 (2016).

    PubMed  PubMed Central  Google Scholar 

  84. Poynter, J. N., Hooten, A. J., Frazier, A. L. & Ross, J. A. Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors. Genes Chromosomes Cancer 51, 266–271 (2012).

    CAS  PubMed  Google Scholar 

  85. Marcotte, E. L. et al. Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children’s oncology group. Genes Chromosomes Cancer 56, 548–558 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang, L. et al. Novel somatic and germline mutations in intracranial germ cell tumours. Nature 511, 241–245 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Looijenga, L. H. Testicular germ cell tumors. Pediatr. Endocrinol. Rev. 11(Suppl 2), 251–262 (2014).

    PubMed  Google Scholar 

  88. Youngren, K. K. et al. The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours. Nature 435, 360–364 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wylie, C. Germ cells. Cell 96, 165–174 (1999).

    CAS  PubMed  Google Scholar 

  90. Kersemaekers, A. M. et al. Identification of germ cells at risk for neoplastic transformation in gonadoblastoma: an immunohistochemical study for OCT3/4 and TSPY. Hum. Pathol. 36, 512–521 (2005).

    CAS  PubMed  Google Scholar 

  91. Cools, M. & Looijenga, L. H. Tumor risk and clinical follow-up in patients with disorders of sex development. Pediatr. Endocrinol. Rev. 9(Suppl 1), 519–524 (2011).

    PubMed  Google Scholar 

  92. Ulbright, T. M. & Young, R. H. Gonadoblastoma and selected other aspects of gonadal pathology in young patients with disorders of sex development. Semin. Diagn. Pathol. 31, 427–440 (2014).

    PubMed  Google Scholar 

  93. Koster, R. et al. Pathway-based analysis of GWAS data identifies association of sex determination genes with susceptibility to testicular germ cell tumors. Hum. Mol. Genet. 23, 6061–6068 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Oosterhuis, J. W. & Looijenga, L. H. The biology of human germ cell tumours: retrospective speculations and new prospectives. Eur. Urol. 23, 245–250 (1993).

    CAS  PubMed  Google Scholar 

  95. Matsui, Y., Zsebo, K. & Hogan, B. L. Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70, 841–847 (1992).

    CAS  PubMed  Google Scholar 

  96. de Jong, J. et al. Further characterization of the first seminoma cell line TCam-2. Genes Chromosomes Cancer 47, 185–196 (2008). An extensive characterization of the only seminoma cell line reported so far.

    PubMed  Google Scholar 

  97. Rajpert-De Meyts, E. Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. Hum. Reprod. Update 12, 303–323 (2006).

    CAS  PubMed  Google Scholar 

  98. Oosterhuis, J. W. et al. A pathologist’s view on the testis biopsy. Int. J. Androl. 34, e14–e19 (2011).

    CAS  PubMed  Google Scholar 

  99. Cools, M., Drop, S. L., Wolffenbuttel, K. P., Oosterhuis, J. W. & Looijenga, L. H. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr. Rev. 27, 468–484 (2006).

    CAS  PubMed  Google Scholar 

  100. Cools, M. et al. Gonadoblastoma arising in undifferentiated gonadal tissue within dysgenetic gonads. J. Clin. Endocrinol. Metab. 91, 2404–2413 (2006).

    CAS  PubMed  Google Scholar 

  101. Cools, M. et al. Impact of the Y-containing cell line on histological differentiation patterns in dysgenetic gonads. Clin. Endocrinol. 67, 184–192 (2007).

    CAS  Google Scholar 

  102. Skakkebaek, N. E., Rajpert-De Meyts, E. & Main, K. M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum. Reprod. 16, 972–978 (2001).

    CAS  PubMed  Google Scholar 

  103. Dalgaard, M. D. et al. A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation. J. Med. Genet. 49, 58–65 (2012).

    PubMed  Google Scholar 

  104. Rajpert-De Meyts, E. & Skotheim, R. I. Complex polygenic nature of testicular germ cell cancer suggests multifactorial aetiology. Eur. Urol. 73, 832–833 (2018).

    PubMed  Google Scholar 

  105. Rajpert-De Meyts, E., McGlynn, K. A., Okamoto, K., Jewett, M. A. & Bokemeyer, C. Testicular germ cell tumours. Lancet 387, 1762–1774 (2016).

    PubMed  Google Scholar 

  106. Kwon, A. et al. Risk of gonadoblastoma development in patients with turner syndrome with cryptic Y chromosome material. Horm. Cancer 8, 166–173 (2017).

    CAS  PubMed  Google Scholar 

  107. Oliveira, R. M. et al. Y chromosome in turner syndrome: review of the literature. Sao Paulo Med. J. 127, 373–378 (2009).

    PubMed  Google Scholar 

  108. Kehler, J. et al. Oct4 is required for primordial germ cell survival. EMBO Rep. 5, 1078–1083 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Oram, S. W., Liu, X. X., Lee, T. L., Chan, W. Y. & Lau, Y. F. TSPY potentiates cell proliferation and tumorigenesis by promoting cell cycle progression in HeLa and NIH3T3 cells. BMC Cancer 6, 154 (2006).

    PubMed  PubMed Central  Google Scholar 

  110. Stang, A. et al. Gonadal and extragonadal germ cell tumours in the United States, 1973–2007. Int. J. Androl. 35, 616–625 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Hersmus, R. et al. Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas. PLoS ONE 7, e43952 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Shahsiah, R. et al. Malignant ovarian germ cell tumours in gonadal Y chromosome mosaicism. J. Clin. Pathol. 64, 973–976 (2011).

    CAS  PubMed  Google Scholar 

  113. Hoei-Hansen, C. E. et al. Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol. Cancer 6, 12 (2007).

    PubMed  PubMed Central  Google Scholar 

  114. Matson, C. K. et al. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476, 101–104 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lindeman, R. E. et al. Sexual cell-fate reprogramming in the ovary by DMRT1. Curr. Biol. 25, 764–771 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Shen, H. et al. Integrated molecular characterization of testicular germ cell tumors. Cell Rep. 23, 3392–3406 (2018). A large, comprehensive molecular study of testicular type II GCTs confirming the rarity of somatic mutations in these tumours, reaching significance only for mutations in KIT, KRAS and NRAS , and only when a seminoma component was present.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Krentz, A. D. et al. The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency. Proc. Natl Acad. Sci. USA 106, 22323–22328 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Meng, X., de Rooij, D. G., Westerdahl, K., Saarma, M. & Sariola, H. Promotion of seminomatous tumors by targeted overexpression of glial cell line-derived neurotrophic factor in mouse testis. Cancer Res. 61, 3267–3271 (2001).

    CAS  PubMed  Google Scholar 

  119. Sariola, H. & Meng, X. GDNF-induced seminomatous tumours in mouse-an experimental model for human seminomas? APMIS 111, 192–196 (2003).

    CAS  PubMed  Google Scholar 

  120. Goriely, A. et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat. Genet. 41, 1247–1252 (2009). A fundamental study identifying paternal age-related mutations in FGFR3 and HRAS as risk factors for spermatocytic tumours.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Looijenga, L. H. et al. POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors. Cancer Res. 63, 2244–2250 (2003).

    CAS  PubMed  Google Scholar 

  122. Matson, C. K. et al. The mammalian doublesex homolog DMRT1 is a transcriptional gatekeeper that controls the mitosis versus meiosis decision in male germ cells. Dev. Cell 19, 612–624 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kanetsky, P. A. et al. Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat. Genet. 41, 811–815 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Rapley, E. A. et al. A genome-wide association study of testicular germ cell tumor. Nat. Genet. 41, 807–810 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Litchfield, K. et al. Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nat. Genet. 49, 1133–1140 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Basten, S. G. et al. Mutations in LRRC50 predispose zebrafish and humans to seminomas. PLoS Genet. 9, e1003384 (2013). This study describes a zebrafish model of seminoma; the tumour is probably an intermediate between a spermatocytic tumour and seminoma, as it does not seem to undergo reprogramming to non-seminoma.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Litchfield, K. et al. Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility. Nat. Commun. 7, 13840 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Giambartolomei, C., Mueller, C. M., Greene, M. H. & Korde, L. A. A mini-review of familial ovarian germ cell tumors: an additional manifestation of the familial testicular germ cell tumor syndrome. Cancer Epidemiol. 33, 31–36 (2009).

    PubMed  PubMed Central  Google Scholar 

  129. Loveday, C. et al. Large-scale analysis demonstrates familial testicular cancer to have polygenic aetiology. Eur. Urol. 74, 248–252 (2018).

    PubMed  Google Scholar 

  130. Liu, L. et al. MCAF1/AM is involved in Sp1-mediated maintenance of cancer-associated telomerase activity. J. Biol. Chem. 284, 5165–5174 (2009).

    CAS  PubMed  Google Scholar 

  131. Cools, M. et al. Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling. Hum. Reprod. 32, 2561–2573 (2017).

    CAS  PubMed  Google Scholar 

  132. Hoeffel, C. C. et al. Fetus in fetu: a case report and literature review. Pediatrics 105, 1335–1344 (2000).

    CAS  PubMed  Google Scholar 

  133. Brand, A. et al. Fetus in fetu-diagnostic criteria and differential diagnosis-a case report and literature review. J. Pediatr. Surg. 39, 616–618 (2004).

    PubMed  Google Scholar 

  134. Kajii, T. & Ohama, K. Androgenetic origin of hydatidiform mole. Nature 268, 633–634 (1977).

    CAS  PubMed  Google Scholar 

  135. Lipata, F. et al. Precise DNA genotyping diagnosis of hydatidiform mole. Obstet. Gynecol. 115, 784–794 (2010).

    PubMed  Google Scholar 

  136. Cutcutache, I. et al. Exome-wide sequencing shows low mutation rates and identifies novel mutated genes in seminomas. Eur. Urol. 68, 77–83 (2015).

    CAS  PubMed  Google Scholar 

  137. Litchfield, K. et al. Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat. Commun. 6, 5973 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Taylor-Weiner, A. et al. Genomic evolution and chemoresistance in germ-cell tumours. Nature 540, 114–118 (2016). This study applies whole-exome and transcriptome sequencing to precursor lesions, primary tumours and metastatic chemoresistant type II GCTs to demonstrate a role for high mitochondrial priming in the chemosensitivity of type II GCTs.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Voorhoeve, P. M. et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124, 1169–1181 (2006).

    CAS  PubMed  Google Scholar 

  140. Bae, Y. U. et al. Embryonic stem cell-derived mmu-miR-291a-3p inhibits cellular senescence in human dermal fibroblasts through the TGF-receptor 2 pathway. J. Gerontol. A. Biol. Sci. Med. Sci. https://doi.org/10.1093/gerona/gly208 (2018).

    Google Scholar 

  141. Bagrodia, A. et al. Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors. J. Clin. Oncol. 34, 4000–4007 (2016). An unbiased next-generation sequencing study of a large population of therapy-resistant patients, showing that cisplatin resistance of type II GCTs is significantly associated with inactivation of p53.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. McIntyre, A. et al. Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults. Cancer Res. 65, 8085–8089 (2005).

    CAS  PubMed  Google Scholar 

  143. Dorssers, L. C. J. et al. Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development. Br. J. Cancer 120, 444–452 (2019). A next-generation sequencing study of clonal evolution of non-seminomas from a precursor lesion through to resistant metastatic disease.

    PubMed  PubMed Central  Google Scholar 

  144. Przygodzki, R. M., Hubbs, A. E., Zhao, F. Q. & O’Leary, T. J. Primary mediastinal seminomas: evidence of single and multiple KIT mutations. Lab. Invest. 82, 1369–1375 (2002).

    CAS  PubMed  Google Scholar 

  145. Oosterhuis, J. W. et al. Ploidy of primary germ cell tumors of the testis. Pathogenetic and clinical relevance. Lab. Invest. 60, 14–21 (1989).

    CAS  PubMed  Google Scholar 

  146. de Jong, B., Oosterhuis, J. W., Castedo, S. M., Vos, A. & te Meerman, G. J. Pathogenesis of adult testicular germ cell tumors. A cytogenetic model. Cancer Genet. Cytogenet. 48, 143–167 (1990).

    PubMed  Google Scholar 

  147. Geurts van Kessel, A. et al. Chromosome 12q heterozygosity is retained in i(12p)-positive testicular germ cell tumor cells. Cancer Genet. Cytogenet. 40, 129–134 (1989).

    CAS  PubMed  Google Scholar 

  148. van Echten, J. et al. No recurrent structural abnormalities apart from i(12p) in primary germ cell tumors of the adult testis. Genes Chromosomes Cancer 14, 133–144 (1995).

    PubMed  Google Scholar 

  149. Ulbright, T. M. in WHO Classification of Tumours of the Urinary System and Male Genital Organs (ed Moch H.) 189–226 (IARC Press, 2016).

  150. Adamah, D. J. et al. Dysfunction of the mitotic:meiotic switch as a potential cause of neoplastic conversion of primordial germ cells. Int. J. Androl. 29, 219–227 (2006).

    CAS  PubMed  Google Scholar 

  151. Baker, D. E. et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat. Biotechnol. 25, 207–215 (2007).

    CAS  PubMed  Google Scholar 

  152. Maitra, A. et al. Genomic alterations in cultured human embryonic stem cells. Nat. Genet. 37, 1099–1103 (2005).

    CAS  PubMed  Google Scholar 

  153. Spits, C. et al. Recurrent chromosomal abnormalities in human embryonic stem cells. Nat. Biotechnol. 26, 1361–1363 (2008).

    CAS  PubMed  Google Scholar 

  154. Fukunaga, M., Endo, Y. & Ushigome, S. Clinicopathologic study of tetraploid hydropic villous tissues. Arch. Pathol. Lab. Med. 120, 569–572 (1996).

    CAS  PubMed  Google Scholar 

  155. Eden, A., Gaudet, F., Waghmare, A. & Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003).

    CAS  PubMed  Google Scholar 

  156. Castel, S. E. et al. Dicer promotes transcription termination at sites of replication stress to maintain genome stability. Cell 159, 572–583 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Ren, J., Castel, S. E. & Martienssen, R. A. Dicer in action at replication-transcription collisions. Mol. Cell. Oncol. 2, e991224 (2015).

    PubMed  PubMed Central  Google Scholar 

  158. Gilbert, D., Rapley, E. & Shipley, J. Testicular germ cell tumours: predisposition genes and the male germ cell niche. Nat. Rev. Cancer 11, 278–288 (2011).

    CAS  PubMed  Google Scholar 

  159. Stoop, H. et al. Stem cell factor as a novel diagnostic marker for early malignant germ cells. J. Pathol. 216, 43–54 (2008).

    CAS  PubMed  Google Scholar 

  160. Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8, 755–768 (2008).

    CAS  PubMed  Google Scholar 

  161. Lytle, N. K., Barber, A. G. & Reya, T. Stem cell fate in cancer growth, progression and therapy resistance. Nat. Rev. Cancer 18, 669–680 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Samaniego, F. et al. Cytogenetic and molecular analysis of human male germ cell tumors: chromosome 12 abnormalities and gene amplification. Genes Chromosomes Cancer 1, 289–300 (1990).

    CAS  PubMed  Google Scholar 

  163. Lau, S. K., Weiss, L. M. & Chu, P. G. D2-40 immunohistochemistry in the differential diagnosis of seminoma and embryonal carcinoma: a comparative immunohistochemical study with KIT (CD117) and CD30. Mod. Pathol. 20, 320–325 (2007).

    CAS  PubMed  Google Scholar 

  164. Oosterhuis, J. W. et al. Sacral teratoma with late recurrence of yolk sac tumor: human counterpart of embryo or yolk sac derived teratoma? J. Urol. Pathol. 1, 257–267 (1993).

    Google Scholar 

  165. Schneider, D. T. et al. Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents. Genes Chromosomes Cancer 34, 115–125 (2002).

    CAS  PubMed  Google Scholar 

  166. Palmer, R. D. et al. Malignant germ cell tumours of childhood: new associations of genomic imbalance. Br. J. Cancer 96, 667–676 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Mosbech, C. H., Rechnitzer, C., Brok, J. S., Rajpert-De Meyts, E. & Hoei-Hansen, C. E. Recent advances in understanding the etiology and pathogenesis of pediatric germ cell tumors. J. Pediatr. Hematol. Oncol. 36, 263–270 (2014).

    CAS  PubMed  Google Scholar 

  168. Looijenga, L. H. et al. Comparative genomic hybridization of microdissected samples from different stages in the development of a seminoma and a non-seminoma. J. Pathol. 191, 187–192 (2000).

    CAS  PubMed  Google Scholar 

  169. Fritsch, M. K., Schneider, D. T., Schuster, A. E., Murdoch, F. E. & Perlman, E. J. Activation of Wnt/beta-catenin signaling in distinct histologic subtypes of human germ cell tumors. Pediatr. Dev. Pathol. 9, 115–131 (2006).

    CAS  PubMed  Google Scholar 

  170. Fustino, N., Rakheja, D., Ateek, C. S., Neumann, J. C. & Amatruda, J. F. Bone morphogenetic protein signalling activity distinguishes histological subsets of paediatric germ cell tumours. Int. J. Androl. 34, e218–e233 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Eakin, G. S. & Behringer, R. R. Tetraploid development in the mouse. Dev. Dyn. 228, 751–766 (2003).

    PubMed  Google Scholar 

  172. Eakin, G. S., Hadjantonakis, A. K., Papaioannou, V. E. & Behringer, R. R. Developmental potential and behavior of tetraploid cells in the mouse embryo. Dev. Biol. 288, 150–159 (2005).

    CAS  PubMed  Google Scholar 

  173. Hu, D. & Cross, J. C. Development and function of trophoblast giant cells in the rodent placenta. Int. J. Dev. Biol. 54, 341–354 (2010).

    CAS  PubMed  Google Scholar 

  174. Floyd, C., Ayala, A. G., Logothetis, C. J. & Silva, E. G. Spermatocytic seminoma with associated sarcoma of the testis. Cancer 61, 409–414 (1988).

    CAS  PubMed  Google Scholar 

  175. Ngan, H. Y. et al. Trophoblastic disease. Int. J. Gynaecol. Obstet. 119 (Suppl 2), S130–S136 (2012).

    PubMed  Google Scholar 

  176. Noguera, R., Navarro, S., Carda, C., Peydro-Olaya, A. & Llombart-Bosch, A. Near-haploidy in a malignant sacrococcygeal teratoma. Cancer Genet. Cytogenet. 108, 70–74 (1999).

    CAS  PubMed  Google Scholar 

  177. van Echten, J. et al. Definition of a new entity of malignant extragonadal germ cell tumors. Genes Chromosomes Cancer 12, 8–15 (1995).

    PubMed  Google Scholar 

  178. Heffner, D. K. & Hyams, V. J. Teratocarcinosarcoma (malignant teratoma?) of the nasal cavity and paranasal sinuses: a clinicopathologic study of 20 cases. Cancer 53, 2140–2154 (1984).

    CAS  PubMed  Google Scholar 

  179. Misra, P. et al. Management of sinonasal teratocarcinosarcoma: a systematic review. Am. J. Otolaryngol. 35, 5–11 (2014).

    PubMed  Google Scholar 

  180. Kinjo, T. et al. Histologic and immunohistochemical analyses of alpha-fetoprotein-producing cancer of the stomach. Am. J. Surg. Pathol. 36, 56–65 (2012).

    PubMed  Google Scholar 

  181. Preda, O. et al. Urothelial carcinoma of the renal pelvis with simultaneous trophoblastic and malignant clear cell endodermal-type differentiation. Virchows Arch. 460, 353–356 (2012).

    PubMed  Google Scholar 

  182. Nogales, F. F., Bergeron, C., Carvia, R. E., Alvaro, T. & Fulwood, H. R. Ovarian endometrioid tumors with yolk sac tumor component, an unusual form of ovarian neoplasm. Analysis of six cases. Am. J. Surg. Pathol. 20, 1056–1066 (1996).

    CAS  PubMed  Google Scholar 

  183. Garcia-Galvis, O. F., Cabrera-Ozoria, C., Fernandez, J. A., Stolnicu, S. & Nogales, F. F. Malignant Mullerian mixed tumor of the ovary associated with yolk sac tumor, neuroepithelial and trophoblastic differentiation (teratoid carcinosarcoma). Int. J. Gynecol. Pathol. 27, 515–520 (2008).

    PubMed  Google Scholar 

  184. Nogales, F. F. et al. Germ cell tumour growth patterns originating from clear cell carcinomas of the ovary and endometrium: a comparative immunohistochemical study favouring their origin from somatic stem cells. Histopathology 72, 634–647 (2018).

    PubMed  Google Scholar 

  185. Stadtfeld, M. & Hochedlinger, K. Induced pluripotency: history, mechanisms, and applications. Genes Dev. 24, 2239–2263 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Ben-Porath, I. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40, 499–507 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Kim, J. et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313–324 (2010). This study demonstrates that a MYC-centred regulatory network in ESCs is also active in various cancers and predicts cancer outcome.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Schaub, F. X. et al. Pan-cancer alterations of the MYC oncogene and its proximal network across the cancer genome atlas. Cell Syst. 6, 282–300.e282 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Thomas, J., Adegboyega, P., Iloabachie, K., Mooring, J. W. & Lian, T. Sinonasal teratocarcinosarcoma with yolk sac elements: a neoplasm of somatic or germ cell origin? Ann. Diagn. Pathol. 15, 135–139 (2011).

    PubMed  Google Scholar 

  190. Clark, A. T. et al. Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma. Stem Cells 22, 169–179 (2004).

    CAS  PubMed  Google Scholar 

  191. Korkola, J. E. et al. Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res. 66, 820–827 (2006).

    CAS  PubMed  Google Scholar 

  192. Koster, R. et al. Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. J. Clin. Invest. 120, 3594–3605 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Oosterhuis, J. W. et al. Effects of multiple-drug chemotherapy (cis-diammine-dichloroplatinum, bleomycin, and vinblastine) on the maturation of retroperitoneal lymph node metastases of nonseminomatous germ cell tumors of the testis. No evidence for de novo induction of differentiation. Cancer 51, 408–416 (1983).

    CAS  PubMed  Google Scholar 

  194. Cheng, L. et al. Testicular cancer. Nat. Rev. Dis. Primers 4, 29 (2018).

    PubMed  Google Scholar 

  195. Oosterhuis, J. W. et al. Patient with two secondary somatic-type malignancies in a late recurrence of a testicular non-seminoma: illustration of potential and flaw of the cancer stem cell therapy concept. Int. J. Dev. Biol. 57, 153–157 (2013).

    PubMed  Google Scholar 

  196. Jacobsen, C. & Honecker, F. Cisplatin resistance in germ cell tumours: models and mechanisms. Andrology 3, 111–121 (2015).

    CAS  PubMed  Google Scholar 

  197. Bauer, S. et al. Therapeutic potential of Mdm2 inhibition in malignant germ cell tumours. Eur. Urol. 57, 679–687 (2010).

    CAS  PubMed  Google Scholar 

  198. Koster, R., Timmer-Bosscha, H., Bischoff, R., Gietema, J. A. & de Jong, S. Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway. Cell Death Dis. 2, e148 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Chaganti, R. S. & Houldsworth, J. Genetics and biology of adult human male germ cell tumors. Cancer Res. 60, 1475–1482 (2000).

    CAS  PubMed  Google Scholar 

  200. Bilen, M. A. et al. Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis. Oncotarget 7, 86280–86289 (2016).

    PubMed  PubMed Central  Google Scholar 

  201. Pfankuchen, D. B. et al. Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway. Oncotarget 8, 67553–67566 (2017).

    PubMed  PubMed Central  Google Scholar 

  202. Mueller, T. et al. The impact of the low molecular weight heparin tinzaparin on the sensitization of cisplatin-resistant ovarian cancers-preclinical in vivo evaluation in xenograft tumor models. Molecules 22, E728 (2017).

    PubMed  Google Scholar 

  203. Schmidtova, S., Kalavska, K. & Kucerova, L. Molecular mechanisms of cisplatin chemoresistance and its circumventing in testicular germ cell tumors. Curr. Oncol. Rep. 20, 88 (2018).

    PubMed  Google Scholar 

  204. Feldman, D. R. State-of-the-art management of germ cell tumors. Am. Soc. Clin. Oncol. Educ. Book. 38, 319–323 (2018).

    PubMed  PubMed Central  Google Scholar 

  205. Olson, T. A. et al. Pediatric and adolescent extracranial germ cell tumors: the road to collaboration. J. Clin. Oncol. 33, 3018–3028 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Sasaki, K. et al. Robust in vitro induction of human germ cell fate from pluripotent stem cells. Cell Stem Cell 17, 178–194 (2015).

    CAS  PubMed  Google Scholar 

  207. Williams, L. A. et al. Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours: a report from the Children’s Oncology Group. Br. J. Cancer 119, 864–872 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Newton, C. et al. A multicentre retrospective cohort study of ovarian germ cell tumours: Evidence for chemotherapy de-escalation and alignment of paediatric and adult practice. Eur. J. Cancer 113, 19–27 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Mego, M. et al. Clinical utility of plasma miR-371a-3p in germ cell tumors. J. Cell. Mol. Med. 23, 1128–1136 (2019).

    CAS  PubMed  Google Scholar 

  210. Dieckmann, K. P. et al. Serum levels of microRNA-371a-3p (M371 test) as a new biomarker of testicular germ cell tumors: results of a prospective multicentric study. J. Clin. Oncol. 37, 1412–1423 (2019).

    PubMed  PubMed Central  Google Scholar 

  211. Irie, N., Tang, W. W. & Azim Surani, M. Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis. Reprod. Med. Biol. 13, 203–215 (2014).

    PubMed  PubMed Central  Google Scholar 

  212. Festuccia, N. et al. Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells. Cell Stem Cell 11, 477–490 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Kojima, Y. et al. The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 14, 107–120 (2014).

    CAS  PubMed  Google Scholar 

  214. Gkountela, S. et al. The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat. Cell. Biol. 15, 113–122 (2013).

    CAS  PubMed  Google Scholar 

  215. Anderson, R. A., Fulton, N., Cowan, G., Coutts, S. & Saunders, P. T. Conserved and divergent patterns of expression of DAZL, VASA and OCT4 in the germ cells of the human fetal ovary and testis. BMC Dev. Biol. 7, 136 (2007).

    PubMed  PubMed Central  Google Scholar 

  216. Hajkova, P. et al. Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway. Science 329, 78–82 (2010).

    CAS  PubMed  Google Scholar 

  217. Hirasawa, R. & Feil, R. Genomic imprinting and human disease. Essays Biochem. 48, 187–200 (2010).

    CAS  PubMed  Google Scholar 

  218. Surani, M. A., Barton, S. C. & Norris, M. L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308, 548–550 (1984).

    CAS  PubMed  Google Scholar 

  219. Surani, M. A., Barton, S. C. & Norris, M. L. Nuclear transplantation in the mouse: heritable differences between parental genomes after activation of the embryonic genome. Cell 45, 127–136 (1986).

    CAS  PubMed  Google Scholar 

  220. Hall, J. G. Genomic imprinting: review and relevance to human diseases. Am. J. Hum. Genet. 46, 857–873 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Inui, M., Tamano, M., Kato, T. & Takada, S. CRISPR/Cas9-mediated simultaneous knockout of Dmrt1 and Dmrt3 does not recapitulate the 46,XY gonadal dysgenesis observed in 9p24.3 deletion patients. Biochem. Biophys. Rep. 9, 238–244 (2017).

    PubMed  PubMed Central  Google Scholar 

  222. van Bever, Y. et al. Multiparameter investigation of a 46,XX/46,XY tetragametic chimeric phenotypical male patient with bilateral scrotal ovotestes and ovulatory activity. Sex Dev. 12, 145–154 (2018).

    PubMed  Google Scholar 

  223. van der Zwan, Y. G., Biermann, K., Wolffenbuttel, K. P., Cools, M. & Looijenga, L. H. Gonadal maldevelopment as risk factor for germ cell cancer: towards a clinical decision model. Eur. Urol. 67, 692–701 (2015).

    PubMed  Google Scholar 

  224. Hersmus, R. et al. Delayed recognition of disorders of sex development (DSD): A missed opportunity for early diagnosis of malignant germ cell tumors. Int. J. Endocrinol. 2012, 671209 (2012).

    PubMed  PubMed Central  Google Scholar 

  225. Byskov, A. G. et al. No evidence for the presence of oogonia in the human ovary after their final clearance during the first two years of life. Hum. Reprod. 26, 2129–2139 (2011).

    CAS  PubMed  Google Scholar 

  226. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  227. Kim, J. B. et al. Direct reprogramming of human neural stem cells by OCT4. Nature 461, 649–633 (2009).

    CAS  PubMed  Google Scholar 

  228. Ben-David, U. & Benvenisty, N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat. Rev. Cancer 11, 268–277 (2011).

    CAS  PubMed  Google Scholar 

  229. Blum, B. & Benvenisty, N. The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle 8, 3822–3830 (2009).

    CAS  PubMed  Google Scholar 

  230. Lee, A. S., Tang, C., Rao, M. S., Weissman, I. L. & Wu, J. C. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat. Med. 19, 998–1004 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. International Stem Cell, I. Assessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells. Nat. Commun. 9, 1925 (2018).

    Google Scholar 

  232. Bedel, A. et al. Preventing pluripotent cell teratoma in regenerative medicine applied to hematology disorders. Stem Cells Transl. Med. 6, 382–393 (2017).

    CAS  PubMed  Google Scholar 

  233. Rampoldi, A. et al. Targeted elimination of tumorigenic human pluripotent stem cells using suicide-inducing virus-like particles. ACS Chem. Biol. 13, 2329–2338 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Blanchard, J. W. et al. Replacing reprogramming factors with antibodies selected from combinatorial antibody libraries. Nat. Biotechnol. 35, 960–968 (2017).

    CAS  PubMed  Google Scholar 

  235. Okada, M. et al. Selective elimination of undifferentiated human pluripotent stem cells using pluripotent state-specific immunogenic antigen glypican-3. Biochem. Biophys. Res. Commun. 511, 711–717 (2019).

    CAS  PubMed  Google Scholar 

  236. Cunningham, J. J., Ulbright, T. M., Pera, M. F. & Looijenga, L. H. Lessons from human teratomas to guide development of safe stem cell therapies. Nat. Biotechnol. 30, 849–857 (2012).

    CAS  PubMed  Google Scholar 

  237. Salvatori, D. C. F. et al. The MicroRNA-371 family as plasma biomarkers for monitoring undifferentiated and potentially malignant human pluripotent stem cells in teratoma assays. Stem Cell Rep. 11, 1493–1505 (2018).

    CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the patients and colleagues who over the past 40 years have contributed to their research, and the support received from the Dutch Cancer Society.

Author information

Authors and Affiliations

  1. Laboratory for Experimental Patho-Oncology, Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, Netherlands

    J. Wolter Oosterhuis & Leendert H. J. Looijenga

  2. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Leendert H. J. Looijenga

Authors
  1. J. Wolter Oosterhuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leendert H. J. Looijenga
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.W.O. and L.H.J.L. equally contributed to researching data for the article, discussions of the content, and writing and review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to J. Wolter Oosterhuis.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Cancer thanks C. Turnball, H. Schorle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Retroperitoneal

Located in the retroperitoneum (that is, the anatomical space behind the peritoneal cavity).

Mediastinal

Located in the mediastinum, subdivided into anterior mediastinum (anatomical space between the heart and the thoracic wall) and posterior mediastinum (anatomical space between the heart and the spine).

Seminomatous GCTs

Malignant GCTs composed of transformed primordial germ cells (extragonadal) or gonocytes (testis, ovary and dysgenetic gonad). Tumours of identical histological type are referred to as seminoma in the testis and mediastinum, dysgerminoma in the ovary and germinoma in the brain; collectively the are referred to as seminomatous GCTs.

Non-seminomatous GCTs

Malignant GCTs consisting of embryonal carcinoma, embryoid bodies, teratoma, yolk sac tumour and choriocarcinoma, either as a pure tumour or as part of a mixed tumour with occasional germ line differentiation. Tumours of identical histological type are referred to as non-seminoma in the testis and mediastinum, non-dysgerminoma in the ovary and non-germinoma in the brain; collectively they are referred to as non-seminomatous GCTs.

Pluripotent

The developmental potential of primed embryonal stem cells, capable of forming embryonic somatic tissues, and not readily contributing to extraembryonic tissues and the germ line.

Blastomeres

Cells produced by a cleavage division of the zygote; the first blastomeres still possess the omnipotency of the zygote.

Totipotent

The developmental potential of naive embryonal stem cells, capable of forming embryonic somatic tissues, and extraembryonic tissues (yolk sac and placenta) and the germ line.

Epiblast

One of two distinct layers arising from the inner cell mass in the mammalian blastocyst.

Partial hydatidiform mole

Triploid pregnancy in which a normal ovum is fertilized by two sperm. It results in overgrowth of the placenta, and a thwarted embryo, due to the ‘overdose’ of paternally imprinted genes.

Complete hydatidiform mole

Also known as complete mole, a diploid benign germ cell tumour resulting from fertilization of an empty ovum by two sperm, and composed of trophoblastic tissue; no development of the embryo due to absence of maternal imprinting.

Genomic imprinting

The mechanism whereby the expression of genes may differ depending on the parental origin.

Teratoma

A germ cell tumour composed of mature somatic tissues; depending on the germ cell tumour type, teratomas can be benign (types I and IV), malignant (type II) or both (type VI).

Gonocytes

Primordial germ cells within the genital ridge before sex-specific differentiation.

Germ cell neoplasia in situ

(GCNIS). Formerly known as carcinoma in situ, intratubular germ cell neoplasia of the unclassified type, or testicular intraepithelial neoplasia, an in situ malignant germ cell tumour confined to seminiferous tubules, composed of transformed gonocytes and located in the spermatogonial niche.

Gonadoblastoma

In situ malignant germ cell tumour of dysplastic gonads, composed of transformed gonocytes enveloped by supporting stromal cells, usually granulosa cells.

Spermatogonia

Stem cells of spermatogenesis.

Spermatocytic tumours

Previously referred to as spermatocytic seminomas, benign germ cell tumours composed of postpubertal spermatogenetic cells in which meiosis is blocked.

Parasitic twins

Poorly developed, nearly always monozygotic twins at the attachment sites of conjoined twins, or included within the body, typically in the abdomen or retroperitoneum.

Dermoid cysts

Also known as cystic mature teratomas, in particular when occurring in extragonadal sites; cystic benign tumours of the ovary composed of mature somatic tissues, predominantly from the cranial part of the body.

Parthenogenetically activated

Reprogramming of an egg, without fertilization.

Sacrococcygeal region

Anatomical region encompassing the sacral and coccygeal bones and immediate surroundings.

Telomerase

A ribonucleoprotein that uses its own RNA as a template for adding nucleotides to the ends of chromosomes.

Telomeres

Short repeated sequences of DNA present at the linear ends of chromosomes that are important for ensuring complete replication of chromosome ends and for protecting the ends from fusion and degradation.

Gynogenotes

Zygotes with two haploid sets of maternally imprinted chromosomes.

Bilaterality

Synchronous or asynchronous occurrence of disease (for example, a tumour) in both of paired organs (for example, testes).

Androgenotes

Zygotes with two haploid sets of paternally imprinted chromosomes.

Trophoblast

Cells forming the outer layer of a blastocyst, giving origin to placental tissue.

Dysgenetic gonad

Gonad disturbed in its sex-specific differentiation.

Embryonal carcinoma

(EC). Malignant germ cell tumour composed of transformed embryonic stem cells, so-called embryonal carcinoma cells, the totipotent stem cells of non-seminomas.

Cryptorchidism

Failure of testicular descent into the scrotum.

Hypovirilization

Incompletely developed male phenotype, including gonads.

Hypospadias

Abnormal opening of the urethra along the ventral aspect of the penis.

Disorders of sex differentiation

(DSD). Also referred to as disorders of sex development or differences of sex development, congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical.

Undifferentiated gonad

Embryonic gonad before differentiation towards testis or ovary.

Sex cords

Strands of stromal cells, the precursors of Sertoli and granulosa cells in the undifferentiated gonad, colonized by gonocytes.

Turner syndrome

A condition in which a female is partly or completely missing an X chromosome, characterized by primary hypogonadism and abnormal physical signs, such as a short and webbed neck.

Leydig cells

Stromal cells between the seminiferous tubules of the testis which on stimulation by luteinizing hormone produce testosterone.

Pre-GCNIS

Lesion of the seminiferous tubule at risk of progressing towards GCNIS.

Spermatogenetic cells

Testicular germ cells producing sperm.

Dysgerminomas

The equivalent of seminomas of the testis that occur in the ovary.

Yolk sac tumours

(YSTs). Also known as a primitive endodermal tumour; a malignant germ cell tumour composed of extraembryonic structures (allantois and yolk sac) and/or intraembryonic endodermal derivatives (primitive gut and liver).

Isochromosome

Abnormal chromosome with two short arms or two long arms only, resulting from horizontal instead of vertical division of the centromere.

Mitotic–meiotic switch

Start of meiosis in germ cells.

Angioinvasion

Infiltration of blood vessels by neoplastic cells.

Pioneer factor

Factor able to open compacted chromatin and regulate gene expression in differentiated tissues and during embryonic development.

Choriocarcinoma

Malignant tumour composed of trophoblastic tissue that may originate in the placenta or from a germ cell tumour.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oosterhuis, J.W., Looijenga, L.H.J. Human germ cell tumours from a developmental perspective. Nat Rev Cancer 19, 522–537 (2019). https://doi.org/10.1038/s41568-019-0178-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-019-0178-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer