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Original article
A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects
  1. Sarah Jervis1,
  2. Honglin Song2,
  3. Andrew Lee1,
  4. Ed Dicks2,
  5. Patricia Harrington2,
  6. Caroline Baynes2,
  7. Ranjit Manchanda3,4,
  8. Douglas F Easton1,2,
  9. Ian Jacobs3,5,
  10. Paul P D Pharoah1,2,
  11. Antonis C Antoniou1
  1. 1Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  2. 2Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  3. 3Institute for Women's Health, University College London, London, UK
  4. 4Department of Gynaecological Oncology, St Bartholomew's Hospital
  5. 5Faculty of Medical & Human Sciences, Institute of Human Development, The University of Manchester and Manchester Academic Health Science Centre
  1. Correspondence to Dr Antonis C Antoniou, Strangeways Research Laboratory, Department of Public Health and Primary Care, Worts Causeway, Cambridge CB1 8RN, UK; antonis{at}srl.cam.ac.uk

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.

  • Genetic epidemiology
  • Ovarian Cancer
  • Risk prediction
  • Genome-wide
  • Genetic screening/counselling

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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