Jin et al. Journal of Experimental & Clinical Cancer Research 2010, 29:18 http://www.jeccr.com/content/29/1/18 Page 6 of 8 Figure 4 Sensitivity analysis of the association of C282Y (YY+CY vs. CC) and HCC among alcoholic LC patients of four studies, in which the meta-analysis estimates were computed omitting one study at a time. The results indicated the association was robust. Discussion HH is a common genetic disease in European popula- tions that causes an inappropriately high absorption of iron, leading to the progressive accumulation of iron in the liver. The two missense mutations C282Y of the HFE gene explain most of the cases of HH, a condition characterized by hepatic iron overload. Liver iron accu- mulation leads to reactive oxygen species formation in the liver, thus causing oxidative stress. It has been shown that the wild-type HFE protein forms a stable complex with the transferrin (TF) receptor (TFR), thereby reducing its affinity for TF [32], whereas the HFE 282Tyr mutation almost completely prevents the formation of a complex between the mutant HFE pro- tein and the TFR, allowing a high-affinity TF binding to the TFR. This binding results in an increased cellular uptake of iron. A second missense mutation in the HFE gene, H63D, is found in about 4% of patients with HH, but its role in iron overload is still debated [6]. It has been reported that HCC occurred more in HH patients than in normal populations in some cohort stu- dies [4,33,34]. However, there are also opposite reports that HH had low penetrance and did not increase the risk of HCC [20,35,36]. From the late 1990s, many researchers have explored the relationship between these two mutations and HCC susceptibility by using case-control or cohort studies [7-9,11-19,30]. In 2007, Christina Ellervik and her col- leagues [37] performed a meta-analysis to examine asso- ciations between C282Y and H63D mutations with HCC. The meta-analysis included nine studies and reported that C282Y homozygotes YY versus CC obtained an odds ratio of 11 to HCC occurrence. How- ever, the sample sizes of many studies included in that meta-analysis were too small, leading to low statistical power. From then on, several articles about HFE muta- tions and HCC have been published. We selected nine eligible studies including 1102 cases and 3766 controls to conduct an updated meta-analysis. Because HH is more frequent in northern European populations, the studies on HFE gene mutations and HCC are mainly come from European ethnicities. In this meta-analysis, eight studies were come from Europe and one from Africa. So, the analysis results may be mainly applicable to European populations and it war- rants to be studied in other ethnicities. In this meta-ana- lysis, the frequency of C282Y YY homozygotes was 0.42% (16/3766), and the frequency of CY heterozygotes was 9.32% (351/3766) in all control subjects. The geno- type distribution was consistent with the dbSNP data. H63D genotype distribution was 2.66% (60/2258) and 23.78% (537/2258) for DD homozygotes and HD hetero- zygotes in controls, respectively. As to C282Y, the ORs of allele contrast (Y vs. C) in the six studies [8,10-12,15,31] were larger than 1.0. Among the six studies, four studies [8,10-12] reported a significant association between HCC and the C282Y polymorphism (ORs > 1.0, 95%CIs did not include 1.0). Because the frequency of the homozygous mutation of C282Y is very low, and a large proportion of C282Y