EASL肝癌峰会丨HNF1A基因：解锁肝细胞癌风险的“密钥”——Mohamed Abdel Samie教授专访

本研究共纳入140例受试者：30例非糖尿病HCC患者、30例合并糖尿病的HCC患者、40例无HCV感染或无HCC的糖尿病患者。此外，还纳入了80例年龄性别匹配的健康志愿者作为对照组。所有参与者均接受肝功能检测、肝炎病毒标志物筛查、甲胎蛋白（AFP）、空腹血糖、糖化血红蛋白（HbA1c）检测，并采用实时荧光定量PCR技术进行HNF1A（rs2464196和rs1169310）基因分型。

结果显示，HNF1A rs2464196位点AA基因型在糖尿病组、HCC组、HCC合并糖尿病组的出现频率均显著高于对照组（ P 值分别为0.006、0.018、＜0.001）。显性遗传模型（AA+GA）在上述患者组中的分布也显著高于对照组中的GG基因型。此外，HCC合并糖尿病组AA基因型占比达73%，显著高于单纯糖尿病或HCC组。相比之下，HNF1A rs1169310位点的基因型（TT/TC/CC）及其等位基因（T/C）分布在四组间未见显著差异。

本研究结果表明，HNF1A rs2464196（AA）基因型可能与糖尿病相关，并可能增加携带该基因型的HCV感染者患HCC的风险。相反，HNF1A rs1169310多态性在本研究中未显示显著风险关联。建议开展大规模研究探索HNF1A其他变异位点，以明确该基因在HCC发生中的具体作用机制。

Mohamed Abdel Samie教授： 我的研究主要聚焦于HNF1A在HCV感染者以及糖尿病患者中的作用。研究结果显示，rs2464196位点AA基因型在糖尿病组、HCC组、HCC合并糖尿病组的出现频率均显著高于对照组，HCC合并糖尿病组AA基因型占比达73%，显著高于单纯糖尿病或HCC组。表明HNF1A rs2464196（AA）基因型可能与糖尿病发生相关，并可能增加HCV感染者（尤其是携带该基因型者）的HCC风险。

我认为该基因对中国糖尿病患者群体同样具有研究价值。然而，还需要进一步研究来确定其在HBV相关HCC中的作用，并在HBV感染人群中验证我们的发现。

Oncology Frontier: Your study highlights the role of the HNF1A genotype in the risk of HCC among affected patients. Given the variant genetic backgrounds in different populations, do you think the risk association could differ in other ethnic groups, such as Asian people, where hepatitis B virus (HBV) is more prevalent?

Dr. Mohamed Abdel Samie: Hepatocyte Nuclear Factor 1A (HNF1A) was studied in my research on patients with hepatitis C virus (HCV) as well as in patients with diabetes mellitus. I believe it may also be relevant for patients with diabetes mellitus in China. However, further research is needed to determine its role in HBV-related HCC and to validate our findings in HBV-infected populations.

Mohamed Abdel Samie教授： 若想将基因检测纳入肝癌监测体系，其成本效益需优于AFP检测、超声等现有无创检测手段。我在本次会议上报告了另一项研究，揭示了HNF1A基因变异对HCC患者病情进展的影响及其与血清AFP水平的关系。

这项研究将受试者分为三组：I组（32例HCC患者）、Ⅱ组（36例慢性HCV感染者），Ⅲ组（26例健康志愿者）作为对照组。每位患者均接受全面病史采集、详细临床检查和影像学检查。此外，采用BCLC分期系统对肿瘤进行分期。通过实时PCR对HNF1A基因多态性（rs-2464196和rs-1169310）进行基因分型。

研究发现，与对照组相比，HCC患者（ P =0.002）和慢性HCV感染者（ P =0.004）中HNF1A rs2464196多态性的AA和GA基因型频率最高。关于rs1169310基因多态性，在比较实验组和对照组时，各基因型之间未观察到显著差异。此外，携带rs2464196 AA基因型的HCC患者AFP水平显著升高（≥200 ng/mL），而携带HNF1A rs1169310单核苷酸多态性（SNP）的HCC患者AFP水平无显著相关性。

这项研究结果表明，HNF1的rs2464196多态性与AFP水平升高和HCC疾病进展相关，可能是一个有潜力的预后和诊断遗传指标。

早期发现HCC对根治性治疗至关重要。如果基因检测变得更加普及，将在高危人群识别和筛查策略优化中发挥重要作用。

Oncology Frontier: Your research found that the AA genotype was significantly associated with increased HCC risk. Would you recommend HNF1A genetic testing as part of routine screening for high-risk populations? And if so, how could this be integrated into existing HCC surveillance programs?

Dr. Mohamed Abdel Samie: For genetic testing to be incorporated into HCC surveillance programs, it should be cost-effective and less expensive than other non-invasive markers, such as alpha-fetoprotein (AFP) and ultrasound. However, early detection is crucial for curative therapy, particularly in the early stages of HCC. If genetic testing becomes more accessible, it could play a vital role in identifying high-risk individuals and improving HCC screening strategies.

Mohamed Abdel Samie教授： 遗传易感性确实会受环境因素影响。研究发现，即使在HCV阳性糖尿病患者和无病毒性肝炎的糖尿病患者携带一个HNF1A的等位基因也可能显著增加患HCC的风险。这表明遗传因素会起到一定作用，但代谢、环境因素同样关键。通过生活方式干预管理糖尿病和代谢紊乱，可能有助于降低HNF1A变异对HCC发展的影响。

Oncology Frontier: Diabetes mellitus is increasingly recognized as a co-factor in HCC development. Do you believe lifestyle interventions targeting metabolic factors could modify the genetic risk associated with HNF1A variants, or is the genetic predisposition altered by external factors?

Dr. Mohamed Abdel Samie: Genetic predisposition is influenced by external factors. Our findings indicate that even a single allele of HNF1A may significantly increase the risk of HCC in HCV-positive diabetic patients, as well as in diabetic patients without viral hepatitis. This suggests that genetics play a role, but metabolic and environmental factors are also important. Lifestyle interventions aimed at managing diabetes and metabolic disorders could potentially reduce the impact of HNF1A variants on HCC development.

Mohamed Abdel Samie教授： 埃及和中国两国HBV和HCV的流行率都很高，因此两国之间的合作至关重要。 The Lancet Regional Health Western Pacific 发表的中国第四次全国乙肝血清学调查结果，表明中国一般人群的乙肝表面抗原（HBsAg，其阳性代表存在HBV感染）流行率自1992年的9.72%下降至2020年的5.86%。但仍预估有3 000万人并不知晓自己的病情，且知情患者中也仅有17.33%（300万）正在接受抗病毒治疗，需要临床加以关注和管理。2020年中国HCV感染948.7万人，HCV相关死亡50 841万人。

在世界各国中，埃及的HCV患病率估计最高，为11.9%。据世界卫生组织数据，全球约有2.57亿慢性HBV感染者，其中非洲区和西太平洋区占68%。埃及作为非洲国家，其HBV感染率较高‌。

我们计划开展大规模研究验证HNF1A在不同人群中的作用，需要在更广泛人群中验证单一基因生物标志物的意义。我们期待与中方合作探索HNF1A在不同人群中的HCC风险提示作用。

Oncology Frontier: Considering that China has a high burden of both HCC and HBV, do you see potential for collaborative studies between Egypt and Chinese researchers to validate HNF1A as a biomarker in diverse populations?

Dr. Mohamed Abdel Samie: Yes, collaboration between Egypt and China is essential, given the high prevalence of HBV and HCV in both countries. One of our research objectives is to conduct a large-scale study to validate our findings. The significance of single-gene biomarkers must be confirmed on a broader scale. We welcome joint research projects between Egypt and China to explore the role of HNF1A in HCC risk across different populations.