Journal article
Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age
International Journal of Cancer, Vol.125(1), pp.78-83
2009
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.
Details
- Title
- Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age
- Authors/Creators
- Z. Shi (Author/Creator) - University of Newcastle AustraliaD. Johnstone (Author/Creator) - University of Newcastle AustraliaB.A. Talseth-Palmer (Author/Creator) - University of Newcastle AustraliaT-J Evans (Author/Creator) - Hunter Medical Research InstituteA.D. Spigelman (Author/Creator) - Surgical Professorial Unit, UNSW St. Vincent's Hospital Clinical School, Sydney, New South Wales, AustraliaC. Groombridge (Author/Creator) - Hunter New England Local Health DistrictE.A. Milward (Author/Creator) - University of Newcastle AustraliaJ.K. Olynyk (Author/Creator) - The University of Western AustraliaJ. Suchy (Author/Creator) - International Hereditary Cancer CenterG. Kurzawski (Author/Creator) - International Hereditary Cancer CenterJ. Lubinski (Author/Creator) - International Hereditary Cancer CenterR.J. Scott (Author/Creator) - University of Newcastle Australia
- Publication Details
- International Journal of Cancer, Vol.125(1), pp.78-83
- Publisher
- Wiley-Liss Inc.
- Identifiers
- 991005541117707891
- Copyright
- 2009 UICC
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
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- Citation topics
- 1 Clinical & Life Sciences
- 1.184 Physiology & Metals
- 1.184.573 Iron Metabolism
- Web Of Science research areas
- Oncology
- ESI research areas
- Clinical Medicine