Prostate cancer segregation analyses using 4390 families from UK and Australian population-based studies

Authors

  • Robert J. MacInnis,

    1. Cancer Research UK Genetic Epidemiology Unit, Strangeways Laboratory, University of Cambridge, Cambridge, UK
    2. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia
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  • Antonis C. Antoniou,

    1. Cancer Research UK Genetic Epidemiology Unit, Strangeways Laboratory, University of Cambridge, Cambridge, UK
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  • Rosalind A. Eeles,

    1. The Institute of Cancer Research, Surrey, UK
    2. The Royal Marsden NHS Foundation Trust, Surrey, UK
    3. The Royal Marsden NHS Foundation Trust, London, UK
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  • Gianluca Severi,

    1. Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia
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  • Michelle Guy,

    1. The Institute of Cancer Research, Surrey, UK
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  • Lesley McGuffog,

    1. Cancer Research UK Genetic Epidemiology Unit, Strangeways Laboratory, University of Cambridge, Cambridge, UK
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  • Amanda L. Hall,

    1. The Institute of Cancer Research, Surrey, UK
    2. The Royal Marsden NHS Foundation Trust, Surrey, UK
    3. The Royal Marsden NHS Foundation Trust, London, UK
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  • Lynne T. O'Brien,

    1. The Institute of Cancer Research, Surrey, UK
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  • Rosemary A. Wilkinson,

    1. The Institute of Cancer Research, Surrey, UK
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  • David P. Dearnaley,

    1. The Institute of Cancer Research, Surrey, UK
    2. The Royal Marsden NHS Foundation Trust, Surrey, UK
    3. The Royal Marsden NHS Foundation Trust, London, UK
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  • Audrey T. Ardern-Jones,

    1. The Royal Marsden NHS Foundation Trust, Surrey, UK
    2. The Royal Marsden NHS Foundation Trust, London, UK
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  • Alan Horwich,

    1. The Institute of Cancer Research, Surrey, UK
    2. The Royal Marsden NHS Foundation Trust, Surrey, UK
    3. The Royal Marsden NHS Foundation Trust, London, UK
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  • Vincent S. Khoo,

    1. The Institute of Cancer Research, Surrey, UK
    2. The Royal Marsden NHS Foundation Trust, Surrey, UK
    3. The Royal Marsden NHS Foundation Trust, London, UK
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  • Christopher C. Parker,

    1. The Institute of Cancer Research, Surrey, UK
    2. The Royal Marsden NHS Foundation Trust, Surrey, UK
    3. The Royal Marsden NHS Foundation Trust, London, UK
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  • Robert A. Huddart,

    1. The Institute of Cancer Research, Surrey, UK
    2. The Royal Marsden NHS Foundation Trust, Surrey, UK
    3. The Royal Marsden NHS Foundation Trust, London, UK
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  • Margaret R. McCredie,

    1. Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand
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  • Charmaine Smith,

    1. Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia
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  • Melissa C. Southey,

    1. Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Grattan Street, Melbourne, Victoria, Australia
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  • Margaret P. Staples,

    1. Department of Epidemiology and Preventive Medicine, Monash University Department of Clinical Epidemiology, Cabrini Hospital, Melbourne, Victoria, Australia
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  • Dallas R. English,

    1. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia
    2. Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia
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  • John L. Hopper,

    1. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia
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  • Graham G. Giles,

    1. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia
    2. Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria, Australia
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  • Douglas F. Easton

    Corresponding author
    1. Cancer Research UK Genetic Epidemiology Unit, Strangeways Laboratory, University of Cambridge, Cambridge, UK
    • Cancer Research UK Genetic Epidemiology Unit, Strangeways Laboratory, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN, UK
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Abstract

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11–0.20), with a relative risk for homozygote carriers of 94 (95% CI 46–192), and a polygenic standard deviation of 2.01 (95% CI 1.72–2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes. Genet. Epidemiol. 34:42–50, 2010. © 2009 Wiley-Liss, Inc.

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