Skip to main content
SpringerLink
Log in

Pediatric Medulloblastoma: The Role of Heterozygous Germ-Line Mutations in the NBN Gene

  • Chapter
  • First Online:
Pediatric Cancer, Volume 3

Part of the book series: Pediatric Cancer ((PECA,volume 3))

Abstract

Medulloblastoma is a highly invasive malignancy of the cerebellum (WHO grade IV) with a high tendency to metastasize via cerebrospinal fluid (CSF) pathways, and the most common malignant brain tumor in childhood. At present, multiple molecular dysfunctions are known to be responsible for medulloblastoma formation, including aberrant activation of the Sonic Hedgehog and Wingless signaling pathways. Nonetheless, recent observations that defects in DNA repair pathways can lead to genomic instability in neural progenitor cells and result in medulloblastoma development have underscored the importance of further genome surveillance. Moreover, recent studies evaluating the role of mutational inactivation of DNA repair genes in the development of medulloblastoma indicate that changes within genes coding such proteins as MRE11, RAD50, and NBN, forming the MRN protein complex, seem to be particularly important. Among these, the germ-line mutations detected in pediatric patients with medulloblastoma were found most frequently in the NBN gene, which codes for a protein that is an essential component of the MRN complex. All the mutations had a heterozygous status and were associated with the classic type of this tumor. Epidemiological data show that the NBN gene can be considered a susceptibility factor for cancer development. This is supported by both the fact that the NBN protein participates in the cellular response to DNA damage, and that medulloblastoma is the most frequently reported solid tumor in Nijmegen breakage syndrome patients, who are at increased risk of developing different types of malignancies. This chapter will focus on new findings implicating NBN in medulloblastoma, which have given new insight into signaling pathways involved in the development of this disease.

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

  • Antoccia A, Kobayashi J, Tauchi H, Matsuura S, Komatsu K (2006) Nijmegen breakage syndrome and functions of the responsible protein, NBS1. Genome Dyn 1:191–205

    Article  CAS  PubMed  Google Scholar 

  • Bakhshi S, Cerosaletti KM, Concannon P, Bawle EV, Fontanesi J, Gatti RA, Bhambhani K (2003) Medulloblastoma with adverse reaction to radiation therapy in Nijmegen breakage syndrome. J Pediatr Hematol Oncol 25(3):248–251

    Article  PubMed  Google Scholar 

  • Brasseur B, Dahan K, Beauloye V, Blétard N, Chantrain C, Dupont S, Guarin JL, Vermylen C, Brichard B (2009) Multiple neoplasia in a 15-year-old girl with familial adenomatous polyposis. J Pediatr Hematol Oncol 31(7):530–532

    Article  PubMed  Google Scholar 

  • Brugières L, Pierron G, Chompret A, Paillerets BB, Di Rocco F, Varlet P, Pierre-Kahn A, Caron O, Grill J, Delattre O (2009) Incomplete penetrance of the predisposition to medulloblastoma associated with germ-line SUFU mutations. J Med Genet 47(2):142–144

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Chrzanowska KH, Stumm M, Bialecka M, Saar K, Bernatowska-Matuszkiewicz E, Michalkiewicz J, Barszcz S, Reis A, Wegner RD (1997) Linkage studies exclude the AT-V gene(s) from the translocation break­points in an AT-V patient. Clin Genet 51(5):309–313

    Article  CAS  PubMed  Google Scholar 

  • Chrzanowska KH, Piekutowska-Abramczuk D, Popowska E, Gładkowska-Dura M, Małdyk J, Syczewska M, Krajewska-Walasek M, Goryluk-Kozakiewicz B, Bubała H, Gadomski A, Gaworczyk A, Kazanowska B, Kołtan A, Kuźmicz M, Luszawska-Kutrzeba T, Maciejka-Kapuścińska L, Stolarska M, Stefańska K, Sznurkowska K, Wakulińska A, Wieczorek M, Szczepański T, Kowalczyk J (2006) Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies. Int J Cancer 118(5):1269–1274

    Article  CAS  PubMed  Google Scholar 

  • Ciara E, Piekutowska-Abramczuk D, Popowska E, Grajkowska W, Barszcz S, Perek D, Dembowska-Bagińska B, Perek-Polnik M, Kowalewska E, Czajńska A, Syczewska M, Czornak K, Krajewska-Walasek M, Roszkowski M, Chrzanowska KH (2010) Heterozy­gous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol 119(3):325–334

    Article  CAS  PubMed  Google Scholar 

  • Crawford JR, MacDonald TJ, Packer RJ (2007) Medullo­blastoma in childhood: new biological advances. Lancet Neurol 6(12):1073–1085

    Article  CAS  PubMed  Google Scholar 

  • di Masi A, Antoccia A (2008) NBS1 heterozygosity and cancer risk. Curr Genomics 9(4):275–281

    Article  PubMed  Google Scholar 

  • Distel L, Neubauer S, Varon R, Holter W, Grabenbauer G (2003) Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. Med Pediatr Oncol 41(1):44–48

    Article  PubMed  Google Scholar 

  • Dubuc AM, Northcott PA, Mack S, Witt H, Pfister S, Taylor MD (2010) The genetics of pediatric brain tumors. Curr Neurol Neurosci Rep 10(3):215–223

    Article  CAS  PubMed  Google Scholar 

  • Dumon-Jones V, Frappart PO, Tong WM, Sajithlal G, Hulla W, Schmid G, Herceg Z, Digweed M, Wang ZQ (2003) Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesis. Cancer Res 63(21):7263–7269

    CAS  PubMed  Google Scholar 

  • Dzikiewicz-Krawczyk A (2008) The importance of making ends meet: mutations in genes and altered expression of proteins of the MRN complex and cancer. Mutat Res 659(3):262–273

    Article  CAS  PubMed  Google Scholar 

  • Ellison D (2002) Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol 28(4):257–282

    Article  CAS  PubMed  Google Scholar 

  • Erez A, Ilan T, Amariglio N, Muler I, Brok-Simoni F, Rechavi G, Izraeli S (2002) GLI3 is not mutated commonly in sporadic medulloblastomas. Cancer 95(1):28–31

    Article  CAS  PubMed  Google Scholar 

  • Frappart PO, Tong WM, Demuth I, Radovanovic I, Herceg Z, Aguzzi A, Digweed M, Wang ZQ (2005) An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nat Med 11(5):538–544

    Article  CAS  PubMed  Google Scholar 

  • Guessous F, Li Y, Abounader R (2008) Signaling pathways in medulloblastoma. J Cell Physiol 217(3):577–583

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Grotzer MA, Watanabe T, Hewer E, Pietsch T, Rutkowski S, Ohgaki H (2008) Mutations in the Nijmegen breakage syndrome gene in medulloblastomas. Clin Cancer Res 14(13):4053–4058

    Article  CAS  PubMed  Google Scholar 

  • Koch A, Hrychyk A, Hartmann W, Waha A, Mikeska T, Waha A, Schüller U, Sörensen 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(2):284–291

    Article  CAS  PubMed  Google Scholar 

  • Lee Y, McKinnon PJ (2002) DNA ligase IV suppresses medulloblastoma formation. Cancer Res 62(22):6395–6399

    CAS  PubMed  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 114(2):97–109

    Article  PubMed Central  PubMed  Google Scholar 

  • Mirzoeva OK, Kawaguchi T, Pieper RO (2006) The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity. Mol Cancer Ther 5(11):2757–2766

    Article  CAS  PubMed  Google Scholar 

  • Mosor M, Mosor M, Ziółkowska I, Pernak-Schwarz M, Januszkiewicz-Lewandowska D, Nowak J (2006) Association of the heterozygous germline I171V mutation of the NBS1 gene with childhood acute lymphoblastic leukemia. Leukemia 20(8):1454–1456

    Article  CAS  PubMed  Google Scholar 

  • Northcott PA, Rutka JT, Taylor MD (2010) Genomics of medulloblastoma: from Giemsa-banding to next-generation sequencing in 20 years. Neurosurg Focus 28(1):1–20

    Article  Google Scholar 

  • Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD (2003) Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 95(20):1548–1551

    Article  CAS  PubMed  Google Scholar 

  • Rieber J, Remke M, Hartmann C, Korshunov A, Burkhardt B, Sturm D, Mechtersheimer G, Wittmann A, Greil J, Blattmann C, Witt O, Behnisch W, Halatsch ME, Orakcioglu B, von Deimling A, Lichter P, Kulozik A, Pfister S (2009) Novel oncogene amplifications in tumors from a family with Li-Fraumeni syndrome. Genes Chromosomes Cancer 48(7):558–568

    Article  CAS  PubMed  Google Scholar 

  • Roy S, Raskin L, Raymond VM, Thibodeau SN, Mody RJ, Gruber SB (2009) Pediatric duodenal cancer and biallelic mismatch repair gene mutations. Pediatr Blood Cancer 53(1):116–120

    Article  PubMed  Google Scholar 

  • Saran A (2009) Medulloblastoma: role of developmental pathways, DNA repair signaling, and other players. Curr Mol Med 9(9):1046–1057

    Article  CAS  PubMed  Google Scholar 

  • Schüller U, Koch A, Hartmann W, Garrè ML, Goodyer CG, Cama A, Sörensen N, Wiestler OD, Pietsch T (2005) Subtype-specific expression and genetic alterations of the chemokinereceptor gene CXCR4 in medulloblastomas. Int J Cancer 117(1):82–89

    Article  PubMed  Google Scholar 

  • Seemanova E (1990) An increased risk for malignant neoplasms in heterozygotes for a syndrome of microcephaly, normal intelligence, growth retardation, remarkable facies, immunodeficiency and chromosomal instability. Mutat Res 238(3):321–324

    Article  CAS  PubMed  Google Scholar 

  • Takahashi C, Kanazawa N, Yoshikawa Y, Yoshikawa R, Saitoh Y, Chiyo H, Tanizawa T, Hashimoto-Tamaoki T, Nakano Y (2009) Germline PTCH1 mutations in Japanese basal cell nevus syndrome patients. J Hum Genet 54(7):403–408

    Article  CAS  PubMed  Google Scholar 

  • Taylor MD, Mainprize TG, Rutka JT (2000) Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review. Neurosurgery 47(4):888–901

    Article  CAS  PubMed  Google Scholar 

  • van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C (1996) Nijmegen breakage syndrome. J Med Genet 33(2):153–156

    Article  PubMed  Google Scholar 

  • Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A (1998) Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93(3):467–476

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Genetics, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland

    Krystyna H. Chrzanowska, Joanna Trubicka & Elżbieta Ciara

Authors
  1. Krystyna H. Chrzanowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joanna Trubicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elżbieta Ciara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Krystyna H. Chrzanowska .

Editor information

Editors and Affiliations

  1. Biology, Kean University, Union, 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

Chrzanowska, K.H., Trubicka, J., Ciara, E. (2012). Pediatric Medulloblastoma: The Role of Heterozygous Germ-Line Mutations in the NBN Gene. In: Hayat, M. (eds) Pediatric Cancer, Volume 3. Pediatric Cancer, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4528-5_13

Download citation

Publish with us

Policies and ethics

Search

Navigation