The specific aim of this thesis was to combine data on mutation prevalence and risk from both high risk families and population based series, in order to develop a model for familial breast and ovarian cancer which incorporates both the effects of BRCA1, BRCA2 and other genes. The principal methodology used was segregation analysis and the genetic models were constructed using the computer program MENDEL. The first dataset consisted of 112 families containing two or more relatives with epithelial ovarian cancer. BRCA1 and BRCA2 germline mutations were detected in 50% of these families. When the effects of BRCA1, BRCA2 and a third ovarian cancer susceptibility gene were modelled simultaneously none of the models fitted gave significant evidence for a third gene. BRCA1 and BRCA2 were estimated to account for at least 38 % of the excess familial risk of ovarian cancer. Using data on the families of twelve BRCA1 mutation carriers in a study of 374 ovarian cancer cases unselected for family history, the estimated ovarian cancer risk by age 70 was 66% and the corresponding breast cancer risk was 45%. The breast cancer dataset consisted of 1484 women diagnosed with breast cancer under the age 55 from whom blood samples were analysed for mutations in BRCA1 and BRCA2. Using information on breast and ovarian cancer history in first degree relatives, and on the mutation status of the index cases we estimated the effects of BRCA1, BRCA2, a third gene BRCA3 and a polygenic effect. For this purpose the Hypergeometric Polygenic model was implemented in MENDEL.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:596129 |
| Date | January 2001 |
| Creators | Antoniou, A. C. |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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