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  • Epidemiology
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A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes

Abstract

In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene ‘BRCA3’, and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021–0.125%) and of BRCA2 0.068% (95% CI: 0.033–0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families.

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Acknowledgements

Our calculations were performed on the Hitachi SR2201 located at the University of Cambridge High Performance Computing Facility. This work was supported by grants from The Cancer Research Campaign, the NCI (1R01 CA81203–01A1), the Cambridge Commonwealth Trust, the Overseas Research Studentships, the A.G. Leventis Foundation, and the Raymond and Beverly Sackler Medical Research Centre. The Anglian Breast Cancer Study was funded by the NHS Research and Development. We would like to thank Julian Lispcompe (ABC study Coordinator), Karen Redman (Research Nurse), Vickie Basham and Jane Gregory (mutation analysis). PDP Pharoah is a senior Clinical research Fellow of The Cancer Research Campaign (CRC). BAJ Ponder is a Gibbs Fellow of the CRC. DF Easton is a principal research fellow of the CRC.

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Correspondence to D F Easton.

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Antoniou, A., Pharoah, P., McMullan, G. et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86, 76–83 (2002). https://doi.org/10.1038/sj.bjc.6600008

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