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The genetic epidemiology of prostate cancer and its clinical implications

Key Points

  • Strong evidence from familial and epidemiological studies supports the notion of a genetic predisposition to prostate cancer

  • Rare, moderate-to-highly penetrant genetic variants have been implicated; some of these are associated with poor prognosis

  • Genome-wide association studies (GWAS) have identified common genetic variants associated with prostate cancer development; GWAS in some prostate cancer treatment cohorts have investigated the role of germline variants in different treatment parameters

  • These variants could enable population-based risk stratification, with potentially important public health implications for targeted screening

  • The functional elements and clinical application of these GWAS variants are still under investigation and more understanding is needed to facilitate better risk modelling to tailor and advise screening and treatment strategies according to a patient's individual risk profile

  • International collaborations have been established to enable complex genetic–epidemiological and genetic–clinical questions to be answered

Abstract

Worldwide, familial and epidemiological studies have generated considerable evidence of an inherited component to prostate cancer. Indeed, rare highly penetrant genetic mutations have been implicated. Genome-wide association studies (GWAS) have also identified 76 susceptibility loci associated with prostate cancer risk, which occur commonly but are of low penetrance. However, these mutations interact multiplicatively, which can result in substantially increased risk. Currently, approximately 30% of the familial risk is due to such variants. Evaluating the functional aspects of these variants would contribute to our understanding of prostate cancer aetiology and would enable population risk stratification for screening. Furthermore, understanding the genetic risks of prostate cancer might inform predictions of treatment responses and toxicities, with the goal of personalized therapy. However, risk modelling and clinical translational research are needed before we can translate risk profiles generated from these variants into use in the clinical setting for targeted screening and treatment.

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Figure 1: Genetic architecture of prostate cancer illustrating that susceptibility is highly likely to be due to a mixed model of common and rare genetic variants.
Figure 2: Predicted cumulative risk of prostate cancer for a 50-year-old male with a positive family history (father with prostate cancer), by percentile of the SNP profile using 26 prostate cancer GWAS risk SNPs.
Figure 3: Consortia investigating the genetic susceptibility to prostate cancer.

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Acknowledgements

The authors are supported by funding from The European Community's Seventh Framework Programme under the grant agreement 223175 (grant number Health-F2-2009-223175-COGS), the Genetic Associations and Mechanisms in Oncology (GAME-ON) Initiative (NIH ELLIPSE grant: U19CA148537) and CRUK (Cancer Research United Kingdom) grants C5047/A10692 (PRACTICAL) and C5047/A13232 (IMPACT). The authors are grateful for the support from The Ronald and Rita McAulay Foundation, The Institute of Cancer Research Everyman Campaign and Prostate Cancer UK. The authors acknowledge support from the National Institute for Health Research to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden Foundation NHS Trust. The authors would also like to thank the collaborators in the ELLIPSE, PRACTICAL, IMPACT and COGS consortia.

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R. Eeles and C. Goh contributed equally to this manuscript. R. Eeles, C. Goh, E. Castro, A. A. Al Olama, D. Easton and Z. Kote-Jarai researched the data for the article. R. Eeles, C. Goh and Z. Kote-Jarai discussed the article's content. R. Eeles, C. Goh, E. Castro, E. Bancroft, M. Guy and Z. Kote-Jarai wrote the manuscript, after which it was edited by all authors before submission.

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Correspondence to Rosalind Eeles.

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Competing interests

All the authors are members of the COGS, ELLIPSE, PRACTICAL and IMPACT consortia. R. Eeles, Z. Kote-Jarai. and D. Easton are co-principal investigators of the PRACTICAL consortium. R. Eeles is the principal investigator of the IMPACT study and a co-principal investigator of the Clinical ELLIPSE Consortium (CEC). R. Eeles has received honoraria from Succinct Communications. R. Eeles has received educational grants from Illumina, Janssen-Cilag, Tepnel (now GenProbe) and Vista Diagnostics.

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Eeles, R., Goh, C., Castro, E. et al. The genetic epidemiology of prostate cancer and its clinical implications. Nat Rev Urol 11, 18–31 (2014). https://doi.org/10.1038/nrurol.2013.266

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