title: Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age.
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.
authors.affiliation: Research Centre for Gender, Health and Ageing, University of Newcastle, Callaghan, Australia.
authors.forename: Zumin
authors.initials: Z
authors.lastname: Shi
authors.forename: Daniel
authors.initials: D
authors.lastname: Johnstone
authors.forename: Bente A
authors.initials: BA
authors.lastname: Talseth-Palmer
authors.forename: Tiffany-Jane
authors.initials: TJ
authors.lastname: Evans
authors.forename: Allan D
authors.initials: AD
authors.lastname: Spigelman
authors.forename: Claire
authors.initials: C
authors.lastname: Groombridge
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Milward
authors.forename: John K
authors.initials: JK
authors.lastname: Olynyk
authors.forename: Janina
authors.initials: J
authors.lastname: Suchy
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kurzawski
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
mesh_terms: D000328:Adult; D017668:Age of Onset; D001315:Australia; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D011044:Poland; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins