title: A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects.
abstract: BACKGROUND
  Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations.
  
  
  METHODS
  We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods.
  
  
  RESULTS
  The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs.
  
  
  CONCLUSIONS
  The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process.
authors.affiliation: Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jervis
authors.affiliation: Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Honglin
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Ed
authors.initials: E
authors.lastname: Dicks
authors.affiliation: Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Harrington
authors.affiliation: Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Baynes
authors.affiliation: Institute for Women's Health, University College London, London, UK Department of Gynaecological Oncology, St Bartholomew's Hospital.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Manchanda
authors.affiliation: Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Institute for Women's Health, University College London, London, UK Faculty of Medical & Human Sciences, Institute of Human Development, The University of Manchester and Manchester Academic Health Science Centre.
authors.forename: Ian
authors.initials: I
authors.lastname: Jacobs
authors.affiliation: Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Paul P D
authors.initials: PP
authors.lastname: Pharoah
authors.affiliation: Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
mesh_terms: D000483:Alleles; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005817:Genetic Counseling / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008957:Models, Genetic; D020412:Multifactorial Inheritance / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000175:diagnosis*; D018570:Risk Assessment / Q000379:methods*
keywords: Genetic epidemiology; Genetic screening/counselling; Genome-wide; Ovarian Cancer; Risk prediction