英国埃克塞特大学医学院David Melzer团队研究了血色素沉着症HFE p.C282Y纯合子与肝脏恶性肿瘤的相关性。2020年11月24日，该研究发表在《美国医学会杂志》上。

遗传性血色素沉着症主要由HFE p.C282Y纯合病原体变异引起。临床诊断为遗传性血色素沉着症的个体其肝癌和死亡风险增加，但在社区基因分型中发现的大多数未确诊该病的p.C282Y纯合子的风险尚不清楚。

为了通过HFE突变状态来评估原发性肝癌的发病率和死亡率，2006-2010年，研究组进行了一项队列研究，在英国生物库中招募了451186例年龄为40-70岁、有欧洲血统的参与者，从基线评估一直追踪到2018年1月。将HFE p.C282Y和p.H63D基因型的男性和女性与没有HFE突变的男性和女性进行比较。共同主要结局为原发性肝癌和全因死亡。

451186名参与者的平均年龄为56.8岁，54.3％为女性，平均随访了8.9年。在1294例男性p.C282Y纯合子中，有21例发生了肝恶性肿瘤，其中10例在基线时未诊断出血色素沉着症。与没有HFE突变的男性相比，p.C282Y纯合子男性患肝恶性肿瘤和全因死亡的风险更高。

在75岁以下男性p.C282Y纯合子的寿命表预测中，原发性肝恶性肿瘤的风险为7.2％，显著高于没有突变的男性（0.6％）；死亡风险为19.5％，显著高于没有突变的男性（15.1％）。在1596例女性p.C282Y纯合子中，有3例发生肝恶性肿瘤，60例死亡，但纯合子与肝恶性肿瘤和死亡的相关性没有统计学意义。

研究结果表明，与没有p.C282Y或p.H63D突变的男性相比，具有HFE p.C282Y纯合子的男性发生原发性肝恶性肿瘤和死亡的风险显著增加，但女性纯合子风险未增加。

附：英文原文

Title: Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy

Author: Janice L. Atkins, Luke C. Pilling, Jane A. H. Masoli, Chia-Ling Kuo, Jeremy D. Shearman, Paul C. Adams, David Melzer

Issue&Volume: 2020/11/24

Abstract:

Importance  Hereditary hemochromatosis is predominantly caused by the HFE p.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping.

Objective  To estimate the incidence of primary hepatic carcinoma and death by HFE variant status.

Design, Setting, and Participants  Cohort study of 451186 UK Biobank participants of European ancestry (aged 40-70 years), followed up from baseline assessment (2006-2010) until January 2018.

Exposures  Men and women with HFE p.C282Y and p.H63D genotypes compared with those with neither HFE variants.

Main Outcomes and Measures  Two linked co–primary outcomes (incident primary liver carcinoma and death from any cause) were ascertained from follow-up via hospital inpatient records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data were available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetics substructure. Kaplan-Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75 years by HFE genotype and sex.

Results  A total of 451186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% women) were followed up for a median (interquartile range) of 8.9 (8.3-9.5) years. Among the 1294 male p.C282Y homozygotes, there were 21 incident hepatic malignancies, 10 of which were in participants without a diagnosis of hemochromatosis at baseline. p.C282Y homozygous men had a higher risk of hepatic malignancies (hazard ratio [HR], 10.5 [95% CI, 6.6-16.7]; P<.001) and all-cause mortality (n=88; HR, 1.2 [95% CI, 1.0-1.5]; P=.046) compared with men with neither HFE variant. In lifetables projections for male p.C282Y homozygotes to age 75 years, the risk of primary hepatic malignancy was 7.2% (95% CI, 3.9%-13.1%), compared with 0.6% (95% CI, 0.4%-0.7%) for men with neither variant, and the risk of death was 19.5% (95% CI, 15.8%-24.0%), compared with 15.1% (95% CI, 14.7%-15.5%) among men with neither variant. Among female p.C282Y homozygotes (n=1596), there were 3 incident hepatic malignancies and 60 deaths, but the associations between homozygosity and hepatic malignancy (HR, 2.1 [95% CI, 0.7-6.5]; P=.22) and death (HR, 1.2 [95% CI, 0.9-1.5]; P=.20) were not statistically significant.

Conclusions and Relevance  Among men with HFE p.C282Y homozygosity, there was a significantly increased risk of incident primary hepatic malignancy and death compared with men without p.C282Y or p.H63D variants; there was not a significant association for women. Further research is needed to understand the effects of early diagnosis and treatment.

DOI: 10.1001/jama.2020.21566

Source: https://jamanetwork.com/journals/jama/article-abstract/2773273