Hereditary Hemochromatosis Variant Associations with Incident Nonliver Malignancies: 11-Year Follow-up in UK Biobank

Abstract

Background: In European ancestry populations, iron overload disorder hereditary hemochromatosis is predominantly caused by HFE p.C282Y and p.H63D mutations. Male p.C282Y homozygotes have markedly increased hepatic malignancy incidence, but risks for other cancers in male and female homozygotes are unclear.

Methods: 451,143 UK Biobank European ancestry participants (aged 40-70 years; 54.3% female) were followed (mean 11.6 years) via hospital admissions and national cancer registries. We estimated risks of any incident cancer (other than nonmelanoma and liver cancer) and common incident cancers [bladder, blood (with subanalyses of leukemia and lymphoma), bone, brain, breast, colorectal, kidney, lung, melanoma, esophageal, ovarian, pancreatic, prostate and stomach] in those with p.C282Y and p.H63D genotypes, compared with participants without HFE mutations.

Results: Male p.C282Y homozygotes (n = 2,890, 12.1% with baseline diagnosed hereditary hemochromatosis) had increased incidence of prostate cancer [6.8% vs. 5.4% without mutations; HR = 1.32; 95% confidence interval (CI), 1.07-1.63; P = 0.01; Bonferroni adjusted P = 0.17] during follow-up. In life table estimates from ages 40 to 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). No increases in risks were found for other studied cancers in male or female p.C282Y homozygotes, or in any other p.C282Y/p.H63D genotype groups of either sex.

Conclusions: In a large community sample of male p.C282Y homozygotes, there is suggestive evidence of increased prostate cancer incidence, with no evidence of excess of other studied (nonliver) cancers.

Impact: Replication of results in other large community genotyped cohorts are needed to confirm if clinical monitoring for prostate cancer is necessary in p.C282Y homozygous males.

Figure 1.

Kaplan-Meier curve for the incidence of prostate cancer in male HFE p.C282Y homozygotes compared to those with no mutations. Participants followed from baseline (2006-2010) via electronic medical records: Hospital inpatient data (to March 2021) and cancer registries (to July 2019). Excludes prevalent diagnoses at baseline.