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Variable methylation of the imprinted gene, SNRPN, supports a relationship between intracranial germ cell tumours and neural stem cells

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

Germ cell tumours (GCTs) are a diverse group of neoplasms all of which are generally believed to arise from germ cell progenitors (PGCs). Even those that form in the nervous system are likewise believed to be PGC-derived, despite being found a great distance from the normal location of germ cells. The primary evidence in favour of this model for the origins of intracranial GCTs is that they share molecular features with other GCTs. Those features include shared gene expression and a lack of methylation of imprinted genes, including SNRPN. Contrary to this model, we have proposed that endogenous neural stem cells of the brain are a more likely origin for these tumours. We show here that the lack of methylation of SNRPN that has previously been taken to indicate an origin for GCTs from PGCs is also seen in neural stem cells of mice and humans. We believe that, in the light of these and other recent observations, endogenous neural precursors of the brain are a more plausible origin for intracranial GCTs than are misplaced PGCs.

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References

  1. Gobel U et al (2000) Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups. Ann Oncol 11:263–271

    Article  CAS  PubMed  Google Scholar 

  2. Lieuw K, Haas-Kogan D, Ablin A (2004) Intracranial germ cell tumours. In: Gupta N, Banerjee A, Haas-Kogan D (eds) Pediatric CNS tumors. Springer, Berlin, pp 107–121

  3. Freeman B (2003) The active migration of germ cells in the embryos of mice and men is a myth. Reproduction 125:635–643

    Article  CAS  PubMed  Google Scholar 

  4. Runyan C, Gu Y, Shoemaker A, Looijenga L, Wylie C (2008) 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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Sievers S et al (2005) 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

    Article  CAS  PubMed  Google Scholar 

  7. Rivera MN, Haber DA (2005) Wilms’ tumour: connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer 5:699–712

    Article  CAS  PubMed  Google Scholar 

  8. Zhan S, Shapiro DN, Helman LJ (1995) Loss of imprinting of IGF2 in Ewing’s sarcoma. Oncogene 11:2503–2507

    CAS  PubMed  Google Scholar 

  9. Zhan S, Shapiro DN, Helman LJ (1994) Activation of an imprinted allele of the insulin-like growth factor II gene implicated in rhabdomyosarcoma. J Clin Invest 94:445–448

    Article  CAS  PubMed  Google Scholar 

  10. Kondo M et al (1995) Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene 10:1193–1198

    CAS  PubMed  Google Scholar 

  11. Kohda M et al (2001) Frequent loss of imprinting of IGF2 and MEST in lung adenocarcinoma. Mol Carcinog 31:184–191

    Article  CAS  PubMed  Google Scholar 

  12. Nishihara S et al (2000) Multipoint imprinting analysis in sporadic colorectal cancers with and without microsatellite instability. Int J Oncol 17:317–322

    CAS  PubMed  Google Scholar 

  13. Bussey KJ et al (2001) SNRPN methylation patterns in germ cell tumors as a reflection of primordial germ cell development. Genes Chromosomes Cancer 32:342–352

    Article  CAS  PubMed  Google Scholar 

  14. Oosterhuis JW, Stoop H, Honecker F, Looijenga LH (2007) Why human extragonadal germ cell tumours occur in the midline of the body: old concepts, new perspectives. Int J Androl 30:256–263 discussion 263–264

    Article  PubMed  Google Scholar 

  15. Scotting PJ (2006) Are cranial germ cell tumours really tumours of germ cells? Neuropathol Appl Neurobiol 32: 569–574

    Article  CAS  PubMed  Google Scholar 

  16. Li JY, Lees-Murdock DJ, Xu GL, Walsh CP (2004) Timing of establishment of paternal methylation imprints in the mouse. Genomics 84:952–960

    Article  CAS  PubMed  Google Scholar 

  17. Rugg-Gunn PJ, Ferguson-Smith AC, Pedersen RA (2005) Epigenetic status of human embryonic stem cells. Nat Genet 37:585–587

    Article  CAS  PubMed  Google Scholar 

  18. White HE, Durston VJ, Harvey JF, Cross NCP (2006) Quantitative analysis of SRNPN gene methylation by pyrosequencing as a diagnostic test for Prader–Willi syndrome and angelman syndrome. Clin Chem 52:1005–1013

    Article  CAS  PubMed  Google Scholar 

  19. Hemberger M et al (1998) H19 and Igf2 are expressed and differentially imprinted in neuroectoderm-derived cells in the mouse brain. Dev Genes Evol 208:393–402

    Article  CAS  PubMed  Google Scholar 

  20. Hajkova P et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117:15–23

    Article  CAS  PubMed  Google Scholar 

  21. Donato R et al (2007) Differential development of neuronal physiological responsiveness in two human neural stem cell lines. BMC Neurosci 8:36

    Article  PubMed  Google Scholar 

  22. Schmittwolf C et al (2005) In vivo haematopoietic activity is induced in neurosphere cells by chromatin-modifying agents. EMBO J 24:554–566

    Article  CAS  PubMed  Google Scholar 

  23. Galli R et al (2000) Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci 3:986–991

    Article  CAS  PubMed  Google Scholar 

  24. Clarke DL et al (2000) Generalized potential of adult neural stem cells. Science 288:1660–1663

    Article  CAS  PubMed  Google Scholar 

  25. Denham M et al (2006) Neural stem cells express non-neural markers during embryoid body coculture. Stem Cells 24:918–927

    Article  CAS  PubMed  Google Scholar 

  26. Kim JB et al (2009) Oct4-induced pluripotency in adult neural stem cells. Cell 136:411–419

    Article  CAS  PubMed  Google Scholar 

  27. Kim JB et al (2009) Direct reprogramming of human neural stem cells by OCT4. Nature 461:649–653

    Article  CAS  PubMed  Google Scholar 

  28. Hu JF, Vu TH, Hoffman AR (1995) Differential biallelic activation of 3 Iinsulin-like growth factor-II promoters in the mouse central nervous system. Mol Endocrinol 9:628–636

    Article  CAS  PubMed  Google Scholar 

  29. Pedone PV et al (1994) Parental imprinting of rat insulin-like growth factor-II gene promoters is coordinately regulated. J Biol Chem 269:23970–23975

    CAS  PubMed  Google Scholar 

  30. Pham NV, Nguyen MT, Hu JF, Vu TH, Hoffman AR (1998) Dissociation of IGF2 and H19 imprinting in human brain. Brain Res 810:1–8

    Article  CAS  PubMed  Google Scholar 

  31. Ruau D et al (2008) Pluripotency associated genes are reactivated by chromatin-modifying agents in neurosphere cells. Stem Cells 26:920–926

    Article  CAS  PubMed  Google Scholar 

  32. Mikkelsen TS et al (2008) Dissecting direct reprogramming through integrative genomic analysis. Nature 454:49–55

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We greatly appreciate the support of the Children’s Cancer and Leukaemia Group (CCLG), especially Dr Juliet Hale and Professor Richard Grundy. VA was supported by The Samantha Dickson Brain Tumout Trust. JNJ was supported by Ali’s Dream and Charlie’s Challenge. RDP, JCN and NC are supported by the MRC, CRUK, CLIC Sargent, The Parthenon Trust and Addenbrooke’s Charities.

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Correspondence to Paul J. Scotting.

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Lee, SH., Appleby, V., Jeyapalan, J.N. et al. Variable methylation of the imprinted gene, SNRPN, supports a relationship between intracranial germ cell tumours and neural stem cells. J Neurooncol 101, 419–428 (2011). https://doi.org/10.1007/s11060-010-0275-9

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  • DOI: https://doi.org/10.1007/s11060-010-0275-9

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