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A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects.

Published version
Peer-reviewed

Repository DOI


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Authors

Jervis, Sarah 
Harrington, Patricia 

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.

Description

Keywords

Genetic epidemiology, Genetic screening/counselling, Genome-wide, Ovarian Cancer, Risk prediction, Alleles, Female, Genes, BRCA1, Genes, BRCA2, Genetic Counseling, Genetic Predisposition to Disease, Humans, Models, Genetic, Multifactorial Inheritance, Ovarian Neoplasms, Risk Assessment

Journal Title

J Med Genet

Conference Name

Journal ISSN

0022-2593
1468-6244

Volume Title

Publisher

BMJ
Sponsorship
Multiple Sclerosis Society (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
This work has been supported by grants from Cancer Research UK (C1005/A12677, C12292/A11174, C490/A10119, C490/A10124) including the PROMISE research programme, the Eve Appeal and the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge.