Haemochromatosis (HFE) gene variation and cholangiocarcinoma risk

Background:

The pathogenesis of cholangiocarcinoma (CCA) as the second most common primary liver cancer is still poorly characterized. By contrast, a substantial risk excess for hepatocellular carcinoma is well established in hereditary haemochromatosis, whereas data on genetic CCA risk related to HFE gene variation is virtually non-existing. Of interest, in a small pathology study a high proportion of 35% of biliary differentiated liver cancer in established haemochromatosis was reported, including CCA and hepatocholangiocarcinoma as observed in alpha1-antitrypsin deficiency [1,2]. Therefore, our aim now was to investigate the effects of common HFE gene variation (p.C282Y and p.H63D) on CCA risk in an independent large European cohort.

Patients & methods:

Overall, 224 Caucasian individuals with CCA (women n = 90; age 66.2 ± 11.8 years; 79.5% extrahepatic tumor localization; 77.7% pathological diagnosis) were genotyped. The control group consisted of 355 CCA- and PSC-free individuals (women n = 197; age 60.7 ± 11.1 years). The single nucleotide variants p.C282Y and p.H63D in the HFE gene were genotyped by PCR-based assays with 5'-nuclease and fluorescence detection (TaqMan).

Results:

The genotype frequencies of the p.C282Y and p.H63D variants in the control group were in Hardy-Weinberg equilibrium (p > 0.05). Allele and genotype frequencies for p.C282Y (minor allele frequencies 4.4% vs. 4.0% for controls and cases, respectively; odds ratio (OR)= 1.09; 95% confidence interval (CI)= 0.60 – 1.98: p > 0.05) and p.H63D (minor allele frequencies 14.4% vs. 17.9% for controls and cases, respectively; OR = 0.79; 95% CI = 0.56 – 1.07: p > 0.05) did not demonstrate a significant overrepresentation in the CCA group. Likewise, sub-analyses of compound heterozygous carriers did not indicate an increased genetic risk of CCA (2.5% vs. 1.8% in the control and CCA groups, respectively: p > 0.05).

Conclusions:

Our preliminary data do not support a prominent role of the common HFE gene variants p.C282Y and p.H63D on genetic CCA risk, despite strong functional candidacy. However, taking into account account the low minor allele frequency of the high-impact variant p.C282Y, larger confirmatory cohort studies with higher statistical power might nonetheless be warranted.

References:

[1] Morcos M et al. Am J Clin Pathol 2001;

[2] Mihalache F V et. al. Aliment Pharmacol Ther 2011.