Skip to main content
SpringerLink
Log in

Pediatric CNS Primitive Neuroectodermal Tumor: Role of the WNT Pathway

  • Chapter
  • First Online:
Pediatric Cancer, Volume 2

Part of the book series: Pediatric Cancer ((PECA,volume 2))

  • 1351 Accesses

Abstract

Central nervous system (CNS) primitive ­neuroectodermal tumors (CNS PNET) are high grade, predominantly pediatric, brain tumors. Previously they have been grouped with medulloblastomas, due to their histological similarities. The WNT/β-catenin pathway has been implicated in many tumor types including medulloblastoma. Upon pathway activation, β-catenin (CTNNB1) translocates to the nucleus where it induces transcription of target genes. It is commonly up-regulated in tumors by mutations in the key pathway components APC and CTNNB1. WNT/β-catenin pathway status was investigated by immunohistochemical analysis of CTNNB1 and the pathway target cyclin D1 (CCND1) in 49 CNS PNETs and 46 medulloblastomas. The mutational status of APC and CTNNB1 (β-catenin) was investigated in 33 CNS PNETs and 22 medulloblastomas. β-catenin nuclear localization was seen in 36% of CNS PNETs and 27% of medulloblastomas. A significant correlation was found between CTNNB1 nuclear localization and CCND1 levels. Mutations in CTNNB1 were identified in 4% of CNS PNETs and 20% of medulloblastomas. No mutations were identified in APC. A potential link between the level of nuclear staining and a better prognosis was identified in the CNS PNETs, suggesting that the extent of pathway activation is linked to outcome. The results suggest that the WNT/β-catenin pathway plays an important role in the pathogenesis of CNS PNETs. However, activation is not caused by mutations in CTNNB1 or APC in the majority of CNS PNET cases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, Cameron JL, Wu TT, Hruban RH (2002) Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol 160:1361–1369

    Article  PubMed  CAS  Google Scholar 

  • Baeza N, Masuoka J, Kleihues P, Ohgaki H (2003) AXIN1 mutations but not deletions in cerebellar medulloblastomas. Oncogene 22:632–636

    Article  PubMed  CAS  Google Scholar 

  • Bondi J, Bukholm G, Nesland JM, Bukholm IR (2004) Expression of non-membranous beta-catenin and gamma-catenin, c-Myc and cyclin D1 in relation to patient outcome in human colon adenocarcinomas. APMIS 112:49–56

    Article  PubMed  CAS  Google Scholar 

  • Catasus L, Bussaglia E, Rodrguez I, Gallardo A, Pons C, Irving JA, Prat J (2004) Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas. Hum Pathol 35:1360–1368

    Article  PubMed  CAS  Google Scholar 

  • Chang CH, Housepian EM, Herbert C Jr (1969) An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:1351–1359

    PubMed  CAS  Google Scholar 

  • Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D, Ellison DW (2006) Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis. Cell Cycle 5:2666–2670

    Article  PubMed  CAS  Google Scholar 

  • Eberhart CG, Tihan T, Burger PC (2000) Nuclear localization and mutation of beta-catenin in medulloblastomas. J Neuropathol Exp Neurol 59:333–337

    PubMed  CAS  Google Scholar 

  • Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, Pearson AD, Clifford SC (2005) Beta-catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol 23:7951–7957

    Article  PubMed  CAS  Google Scholar 

  • Geyer JR, Sposto R, Jennings M, Boyett JM, Axtell RA, Breiger D, Broxson E, Donahue B, Finlay JL, Goldwein JW, Heier LA, Johnson D, Mazewski C, Miller DC, Packer R, Puccetti D, Radcliffe J, Tao ML, Shiminski-Maher T (2005) Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol 23:7621–7631

    Article  PubMed  Google Scholar 

  • Haberler C, Varlet P, Legoix P, Fattet S, Janoueix-Lerosey I, Lellouch-Tubiana A, Grill J, Doz F, Sainte-Rose C, Delattre O (2008) Widespread nuclear b-catenin expression in medulloblastoma correlates with mutation status of CTNNB1 gene encoding b-catenin [abstract]. Neuro-oncology 10:470

    Google Scholar 

  • Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, Berger PC, Wood PA, Taqi F, Booker SV, Petersen GM, Offerhaus JA, Tersmette AC, Giardiello FM, Vogelstein B, Kinzler KW (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–847

    Article  PubMed  CAS  Google Scholar 

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512

    Article  PubMed  CAS  Google Scholar 

  • Hommura F, Furuuchi K, Yamazaki K, Ogura S, Kinoshita I, Shimizu M, Moriuchi T, Katoh H, Nishimura M, Dosaka-Akita H (2002) Increased expression of beta-catenin predicts better prognosis in nonsmall cell lung carcinomas. Cancer 94:752–758

    Article  PubMed  CAS  Google Scholar 

  • Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H (2000) APC mutations in sporadic medulloblastomas. Am J Pathol 156:433–437

    Article  PubMed  CAS  Google Scholar 

  • Janssens N, Andries L, Janicot M, Perera T, Bakker A (2004) Alteration of frizzled expression in renal cell carcinoma. Tumour Biol 25:161–171

    Article  PubMed  CAS  Google Scholar 

  • Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T (1999) Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Cancer Res 59:269–273

    PubMed  CAS  Google Scholar 

  • Koch A, Waha A, Tonn JC, Sorensen N, Berthold F, Wolter M, Reifenberger J, Hartmann W, Friedl W, Reifenberger G, Wiestler OD, Pietsch T (2001) Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 93:445–449

    Article  PubMed  CAS  Google Scholar 

  • Koch A, Hrychyk A, Hartmann W, Waha A, Mikeska T, Waha A, Schuller U, Sorensen N, Berthold F, Goodyer CG, Wiestler OD, Birchmeier W, Behrens J, Pietsch T (2007) Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomas. Int J Cancer 121:284–291

    Article  PubMed  CAS  Google Scholar 

  • Kongkham PN, Northcott PA, Croul SE, Smith CA, Taylor MD, Rutka JT (2010) The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma. Oncogene 29:3017. doi:10.1038/onc.2010.32

    Article  PubMed  CAS  Google Scholar 

  • Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG, Hung MC (2000) Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA 97:4262–4266

    Article  PubMed  CAS  Google Scholar 

  • Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Boardman LA, Qian C, Christensen E, Schmidt SS, Roche PC, Smith DI, Thibodeau SN (2000) Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat Genet 26:146–147

    Article  PubMed  CAS  Google Scholar 

  • Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl) 114:97–109

    Article  Google Scholar 

  • Marino S (2005) Medulloblastoma: developmental mechanisms out of control. Trends Mol Med 11:17–22

    Article  PubMed  CAS  Google Scholar 

  • Merle P, de la Monte S, Kim M, Herrmann M, Tanaka S, Von Dem Bussche A, Kew MC, Trepo C, Wands JR (2004) Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 127:1110–1122

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, Nakamura Y (1992) Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1:229–233

    Article  PubMed  CAS  Google Scholar 

  • Morin PJ (1999) Beta-catenin signaling and cancer. Bioessays 21:1021–1030

    Article  PubMed  CAS  Google Scholar 

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790

    Article  PubMed  CAS  Google Scholar 

  • Pizer BL, Weston CL, Robinson KJ, Ellison DW, Ironside J, Saran F, Lashford LS, Tait D, Lucraft H, Walker DA, Bailey CC, Taylor RE (2006) Analysis of patients with supratentorial primitive neuro-ectodermal tumours entered into the SIOP/UKCCSG PNET 3 study. Eur J Cancer 42:1120–1128

    Article  PubMed  Google Scholar 

  • Reddy AT, Janss AJ, Phillips PC, Weiss HL, Packer RJ (2000) Outcome for children with supratentorial ­primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 88:2189–2193

    Article  PubMed  CAS  Google Scholar 

  • Salaroli R, Di Tomaso T, Ronchi A, Ceccarelli C, Cammelli S, Cappellini A, Martinelli GN, Barbieri E, Giangaspero F, Cenacchi G (2008) Radiobiologic response of medulloblastoma cell lines: involvement of beta-catenin? J Neurooncol 90:243–251

    Article  PubMed  CAS  Google Scholar 

  • Saldanha G, Ghura V, Potter L, Fletcher A (2004) Nuclear beta-catenin in basal cell carcinoma correlates with increased proliferation. Br J Dermatol 151:157–164

    Article  PubMed  CAS  Google Scholar 

  • Sure U, Berghorn WJ, Bertalanffy H, Wakabayashi T, Yoshida J, Sugita K, Seeger W (1995) Staging, scoring and grading of medulloblastoma. A postoperative prognosis predicting system based on the cases of a single institute. Acta Neurochir (Wien) 132:59–65

    Article  CAS  Google Scholar 

  • Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, Pretlow TP, Yang B, Akiyama Y, Van Engeland M, Toyota M, Tokino T, Hinoda Y, Imai K, Herman JG, Baylin SB (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417–422

    Article  PubMed  CAS  Google Scholar 

  • Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426

    Article  PubMed  CAS  Google Scholar 

  • Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, Chintagumpala M, Adesina A, Ashley DM, Kellie SJ, Taylor MD, Curran T, Gajjar A, Gilbertson RJ (2006) Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 24:1924–1931

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Brain Tumour Research Centre, Queen’s Medical Centre, University of Nottingham, D Floor Medical School (D32), Nottingham, NG7 2UH, UK

    Hazel A. Rogers & Richard G. Grundy

Authors
  1. Hazel A. Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard G. Grundy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard G. Grundy .

Editor information

Editors and Affiliations

  1. , Kean University, Room 213, Library building, Morris Avenue 1000, Union, 07083, New Jersey, USA

    M.A. Hayat

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Rogers, H.A., Grundy, R.G. (2012). Pediatric CNS Primitive Neuroectodermal Tumor: Role of the WNT Pathway. In: Hayat, M. (eds) Pediatric Cancer, Volume 2. Pediatric Cancer, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2957-5_8

Download citation

Publish with us

Policies and ethics

Search

Navigation