Wilms tumour is a childhood kidney tumour with an incidence of I in 10,000. I investigated a child with bilateral, young-onset Wilms tumour and a de novo 5:6)(q2l;q2l) translocation. Next generation sequencing localized the breakpoints to within 1.7 kb. Using long-range PCR, I identified that HACEI was transected by the 6q breakpoint and was therefore a credible candidate Wilms tumour predisposition gene. I screened HACEI for mutations in 450 Wilms tumour cases and identified one child with a truncating HACEI mutation. These data suggest that HACEl is a rare Wilms tumour predisposition gene. DICERl mutations cause familial pleuropulmonary blastoma (PPB), a rare childhood lung tumour. I sequenced constitutional DNA from a total of 823 cases with various tumour types. I identified DICERL mutations in 19 cases, from a subset of tumour types; 1/114 with PPB,2l3 with cystic nephroma, 417 with ovarian Sertoli- Leydig type tumours, 11243 with Wilms tumour (this individual also had Sertoli- Leydig tumour), l/l with globe medulloepithelioma (this individual also had PPB), 1/86 l/172 medulloblastoma and 11172 with germ cell tumour. Analysis of tumours mutation-positive individuals demonstrated retention of the wild-type allele. I investigated the inheritance in 17 families and identified mutations in 25 relatives; 17 of which were unaffected. Constitutional DICERI haploinsufficiency thus predisposes to a range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours. Most mutation carriers are unaffected indicating that the risk of tumours is modest. institutional mutations in PTCHI and SUFU are associated with childhood medulloblastoma. I investigated the contribution of constitutional PTCHI and SUFU mutations to medulloblastoma by mutational analysis in three familial pedigrees and 83 sporadic cases. I identified no mutations in the familial cases and two truncating SUFL mutations in the sporadic cases. These data indicate that familial medulloblastoma is genetically heterogeneous and that inactivating SUFU mutations cause;:rse approximately 2-3%o of sporadic medulloblastomas
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:546060 |
| Date | January 2011 |
| Creators | Slade, Ingrid |
| Publisher | Institute of Cancer Research (University Of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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