Hereditary haemochromatosis beyond liver cancer: increased risk of prostate cancer during an 11-year follow-up

AbstractIn European ancestry populations, the iron overload disorder Hereditary Haemochromatosis (HH) is predominantly caused by the HFE p.C282Y mutation. Male p.C282Y homozygotes have markedly increased hepatic malignancy risks but risks for other cancers in both male and female homozygotes are unclear. We studied data from 451,143 UK Biobank European ancestry community participants (aged 40-70 years; 54.3% female) followed for a mean 11.6 years via hospital admission and national cancer registry data. We estimated risks of incident bladder, blood (with sub-analyses of leukemia and lymphoma), bone, brain, breast, colorectal, kidney, lung, melanoma, oesophageal, ovarian, pancreatic, prostate and stomach cancers in the 2,890 p.C282Y homozygotes, compared to participants without HFE mutations. Male p.C282Y homozygotes (12.1% with baseline diagnosed HH) had increased risks of prostate cancer (6.8% versus 5.4% without mutations, hazard ratio HR=1.32, 95% CI=1.07-1.63, p=0.01,). In lifetable estimates from ages 40-75 years, 14.4% of male p.C282Y homozygotes are projected to develop prostate cancer (versus 10.7% without mutations, excess 3.8%, 95% CI = 1.3-6.8). There was no excess of studied cancers in female p.C282Y homozygotes, or in p.C282Y/p.H63D compound heterozygotes of either sex. In a large community sample of male p.C282Y homozygotes, there was a 32% increase in prostate cancer risk, in addition to the known increased liver cancer risk. Those reporting HFE genotype status or monitoring p.C282Y homozygous males may need to ensure clinical monitoring for both liver and prostate cancers.Novelty and impact of the workMale HFE p.C282Y homozygotes, at risk of iron overload disorder hereditary haemochromatosis, have known increased liver cancer risks. We have shown, for the first time, that the male p.C282Y homozygotes also have a 32% increased risk of prostate cancer; with an excess proportion of 3.8% by age 75 compared to those without mutations. Those reporting HFE genotype status or monitoring p.C282Y homozygous males need to ensure vigilance for both excess liver and prostate cancers.