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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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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