Polygenic susceptibility to breast cancer and implications for prevention

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Abstract

The knowledge of human genetic variation that will come from the human genome sequence makes feasible a polygenic approach to disease prevention, in which it will be possible to identify individuals as susceptible by their genotype profile and to prevent disease by targeting interventions to those at risk. There is doubt, however, regarding the magnitude of these genetic effects and thus the potential to apply them to either individuals or populations. We have therefore examined the potential for prediction of risk based on common genetic variation using data from a population-based series of individuals with breast cancer. The data are compatible with a log-normal distribution of genetic risk in the population that is sufficiently wide to provide useful discrimination of high- and low-risk groups. Assuming all of the susceptibility genes could be identified, the half of the population at highest risk would account for 88% of all affected individuals. By contrast, if currently identified risk factors for breast cancer were used to stratify the population, the half of the population at highest risk would account for only 62% of all cases. These results suggest that the construction and use of genetic-risk profiles may provide significant improvements in the efficacy of population-based programs of intervention for cancers and other diseases.

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Figure 1: Distribution of breast cancer risk in the population and in individual cases.
Figure 2: Proportion of population above a specified absolute risk of breast cancer and proportion of cases occurring in that fraction of the population.
Figure 3: Proportion of cases accounted for by a given proportion of the population above a specified risk according to the standard deviation of underlying risk distribution.

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Acknowledgements

P.P. is a Senior Clinical Research Fellow, D.F.E. is a Principal Fellow and B.A.J.P. is a Gibb Fellow of Cancer Research UK. The Public Health Genetics Unit is funded by the Eastern Regional Office of the National Health Service Executive. Research in the Strangeways Laboratories is supported by a grant from the National Lottery Board and by program grants from Cancer Research UK and the Medical Research Council. We thank H. Burton, C. Brayne, M. Austin and N. Day for their helpful comments on early drafts of this manuscript.

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Correspondence to Paul D.P. Pharoah.

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