Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age

Authors

  • Zumin Shi,

    1. Research Centre for Gender, Health and Ageing, University of Newcastle, Callaghan, Australia
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    • The first two authors contributed equally to this work.

  • Daniel Johnstone,

    1. Research Centre for Gender, Health and Ageing, University of Newcastle, Callaghan, Australia
    2. School of Biomedical Sciences, University of Newcastle, Callaghan, Australia
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    • The first two authors contributed equally to this work.

  • Bente A. Talseth-Palmer,

    1. School of Biomedical Sciences, University of Newcastle, Callaghan, Australia
    2. Hunter Medical Research Institute, New South Wales, Australia
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  • Tiffany-Jane Evans,

    1. Hunter Medical Research Institute, New South Wales, Australia
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  • Allan D. Spigelman,

    1. Surgical Professorial Unit, UNSW St. Vincent's Hospital Clinical School, Sydney, New South Wales, Australia
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  • Claire Groombridge,

    1. Hunter Family Cancer Service, Hunter New England Health, Newcastle, New South Wales, Australia
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  • Elizabeth A. Milward,

    1. Research Centre for Gender, Health and Ageing, University of Newcastle, Callaghan, Australia
    2. School of Biomedical Sciences, University of Newcastle, Callaghan, Australia
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  • John K. Olynyk,

    1. School of Medicine and Pharmacology, University of Western Australia, and The Western Australian Institute of Medical Research, Nedlands, Australia
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  • Janina Suchy,

    1. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Academy of Medicine, Szczecin, Poland
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  • Grzegorz Kurzawski,

    1. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Academy of Medicine, Szczecin, Poland
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  • Jan Lubinski,

    1. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Academy of Medicine, Szczecin, Poland
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  • Rodney J. Scott

    Corresponding author
    1. School of Biomedical Sciences, University of Newcastle, Callaghan, Australia
    2. Hunter Medical Research Institute, New South Wales, Australia
    3. Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia
    • Hunter Area Pathology Service, John Hunter Hospital, Lookout Rd., New Lambton Heights, New South Wales 2305, Australia
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    • Fax: +61-2-4921-4253.


Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes; however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 individuals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian sample only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC. © 2009 UICC

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