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Heterogeneity of familial medulloblastoma and contribution of germline PTCH1 and SUFU mutations to sporadic medulloblastoma

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Abstract

PTCH1 and SUFU are both regulators of the sonic hedgehog signalling pathway. Germline inactivating mutations in both genes are associated with multisystem phenotypes including medulloblastoma. Somatic inactivating mutations in PTCH1 and SUFU each occur in approximately 10% of medulloblastomas. Recently, SUFU mutations were reported in familial medulloblastoma pedigrees without additional phenotypic features. We sought to further investigate the contribution of germline PTCH1 and SUFU mutations to familial and sporadic medulloblastoma. We performed full-gene mutational analysis of both PTCH1 and SUFU in three familial medulloblastoma pedigrees and 83 individuals with sporadic non-familial medulloblastoma. We identified no mutations in PTCH1 or SUFU in the three familial medulloblastoma pedigrees. We identified no PTCH1 mutations and two SUFU mutations that cause premature protein truncating in the series of sporadic non-familial medulloblastomas. The SUFU mutations were identified in two of the 16 individuals with desmoplastic medulloblastomas. These data indicate that familial medulloblastoma is a genetically heterogeneous disorder with at least one further susceptibility gene to be discovered. Furthermore, although both PTCH1 and SUFU play a key role in the sonic hedgehog signalling pathway, PTCH1 does not make an appreciable contribution to non-familial sporadic medulloblastoma, whereas inactivating germline mutations of SUFU cause ~2–3% of sporadic medulloblastomas and > 10% of desmoplastic medulloblastomas.

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Abbreviations

MBEN:

Medulloblastoma with extensive nodularity

NBCCS:

Nevoid basal cell carcinoma syndrome

CCLG:

Children’s cancer and leukaemia group

PCR:

Polymerase chain reaction

References

  1. Pfister S, Hartmann C, Korshunov A (2009) Histology and molecular pathology of pediatric brain tumors. J Child Neurol 24(11):1375–1386

    Article  PubMed  Google Scholar 

  2. Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109

    Article  PubMed  Google Scholar 

  3. Rousseau A, Mokhtari K, Duyckaerts C (2008) The 2007 WHO classification of tumors of the central nervous system—what has changed? Curr Opin Neurol 21(6):720–727

    Article  PubMed  Google Scholar 

  4. McManamy CS, Pears J, Weston CL et al (2007) Nodule formation and desmoplasia in medulloblastomas-defining the nodular/desmoplastic variant and its biological behavior. Brain Pathol 17(2):151–164

    Article  PubMed  Google Scholar 

  5. Cowan R, Hoban P, Kelsey A, Birch JM, Gattamaneni R, Evans DG (1997) The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma. Br J Cancer 76(2):141–145

    Article  PubMed  CAS  Google Scholar 

  6. Amlashi SF, Riffaud L, Brassier G, Morandi X (2003) Nevoid basal cell carcinoma syndrome: relation with desmoplastic medulloblastoma in infancy. A population-based study and review of the literature. Cancer 98(3):618–624

    Article  PubMed  Google Scholar 

  7. Zurawel RH, Allen C, Chiappa S et al (2000) Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosomes Cancer 27(1):44–51

    Article  PubMed  CAS  Google Scholar 

  8. Taylor MD, Liu L, Raffel C et al (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31(3):306–310

    Article  PubMed  CAS  Google Scholar 

  9. Pastorino L, Ghiorzo P, Nasti S et al (2009) Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am J Med Genet A 149A(7):1539–1543

    Article  PubMed  CAS  Google Scholar 

  10. Moschovi M, Sotiris Y, Prodromou N et al (1998) Familial medulloblastoma. Pediatr Hematol Oncol 15(5):421–424

    Article  PubMed  CAS  Google Scholar 

  11. von Koch CS, Gulati M, Aldape K, Berger MS (2002) Familial medulloblastoma: case report of one family and review of the literature. Neurosurgery 51(1): 227–233 (discussion 33)

    Google Scholar 

  12. Brugieres L, Pierron G, Chompret A et al (2010) Incomplete penetrance of the predisposition to medulloblastoma associated with germ-line SUFU mutations. J Med Genet 47(2):142–144

    Article  PubMed  CAS  Google Scholar 

  13. Pasca di Magliano M, Hebrok M (2003) Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 3(12):903–911

    Article  PubMed  Google Scholar 

  14. Toftgard R (2000) Hedgehog signalling in cancer. Cell Mol Life Sci 57(12):1720–1731

    Article  PubMed  CAS  Google Scholar 

  15. Rubin JB, Rowitch DH (2002) Medulloblastoma: a problem of developmental biology. Cancer Cell 2(1):7–8

    Article  PubMed  CAS  Google Scholar 

  16. Entz-Werle N, Carli ED, Ducassou S, Legrain M, Grill J, Dufour C (2008) Medulloblastoma: what is the role of molecular genetics? Expert Rev Anticancer Ther 8(7):1169–1181

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Brenner DJ, Quan H (1990) Exact confidence limits for binomial proportions—Pearson and Hartley revisited. Statistician 39:391–397

    Article  Google Scholar 

  20. Kimonis VE, Goldstein AM, Pastakia B et al (1997) Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 69(3):299–308

    Article  PubMed  CAS  Google Scholar 

  21. Ng D, Stavrou T, Liu L et al (2005) Retrospective family study of childhood medulloblastoma. Am J Med Genet A 134(4):399–403

    PubMed  Google Scholar 

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Acknowledgments

We thank the children and families involved in the research and the physicians, nurses and pathologists who referred families and provided samples. We thank Nikki Huxter, Margaret Warren-Perry, Darshna Dudakia, Polly Gibbs, Jessie Bull and Anna Zachariou for assistance of recruitment. We thank Bernadette Ebbs and Deborah Hughes for running the ABI sequencers. The research was carried out as part of the Factors Associated with Childhood Tumors (FACT) study, which is a UK Children’s Cancer and Leukaemia Group (CCLG) study. The Childhood Cancer Research Group receives funding from the Department of Health and the Scottish Ministers. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health and the Scottish Ministers. I.S. is supported by the Michael and Betty Kadoorie Cancer Genetics Research Programme. We acknowledge NHS funding to the NIHR Biomedical Research Centre. This work was supported by Cancer Research UK (grants C8620_A9024 and C8620_A8857) and the Institute of Cancer Research (UK).

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Correspondence to Nazneen Rahman.

Additional information

Accession numbers: The cDNA Genbank accession number for the PTCH1 sequence reported in this paper is NM_000264 and for the SUFU sequence reported in this paper is NM_016169.

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Slade, I., Murray, A., Hanks, S. et al. Heterogeneity of familial medulloblastoma and contribution of germline PTCH1 and SUFU mutations to sporadic medulloblastoma. Familial Cancer 10, 337–342 (2011). https://doi.org/10.1007/s10689-010-9411-0

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