Clinical and Experimental Pharmacology, "Centro di Riferimento Oncologico" - National Cancer Institute, 33081 Aviano, Italy.
Unit of Cancer Epidemiology, "Centro di Riferimento Oncologico" - National Cancer Institute, 33081 Aviano, Italy.
World J Gastroenterol. 2017 Sep 28;23(36):6674-6684. doi: 10.3748/wjg.v23.i36.6674.
To uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma (HCC) susceptibility in Caucasians.
The present retrospective case-control study compared genotype frequencies between a cohort of HCC cases and two, independent, HCC-free, age/sex-matched control groups. The HCC cohort comprised 192 homogeneous patients that had undergone orthotopic liver transplantation. The first control group comprised 167 patients that were matched to the HCC cohort for the percentage of hepatitis B (HBV) and/or hepatitis C (HCV) infections. A second control group included 192 virus-free, healthy individuals that were used to evaluate the generalizability of the identified predictive markers. All cases and controls were Caucasian. The three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related pathways. The study end-point was to assess the association between genetic variants and HCC onset.
Five genetic markers were identified as risk factors for HCC in high-risk patients infected with HBV/HCV. According to a dominant model, reduced HCC risk was associated with three polymorphisms: rs3212986 (OR = 0.46, 95%CI: 0.30-0.71, = 0.0005), rs1138272 (OR = 0.41, 95%CI: 0.21-0.81, = 0.0097), and rs743572 (OR = 0.50, 95%CI: 0.31-0.79, = 0.0032). Conversely, according to a recessive model, increased HCC risk was associated with two polymorphisms: rs1799794 (OR = 3.70, 95%CI: 1.02-13.39, = 0.0461) and rs1128503 (OR = 2.06, 95%CI: 1.18-3.61, = 0.0111). These associations remained significant in a subgroup analysis, where patients were stratified according to viral status (HBV- or HCV-positive serology). Two variants exhibited a serology-specific effect: rs1128503 (OR = 4.18, 95%CI: 1.55-11.29, = 0.0048) showed an effect in the HBV-positive subgroup; and rs3212986 (OR = 0.33, 95%CI: 0.18-0.60, = 0.0003) showed an effect in the HCV-positive subgroup. Among the five markers identified, rs3212986 (OR = 0.43, < 0.0001) and rs743572 (OR = 0.73, = 0.0310) had a different distribution in patients with HCC compared to healthy individuals. With a recursive partitioning approach, we also demonstrated that significant gene-gene interactions between rs3212986, rs743572, rs1138272, and the previously described *3 predictive marker, played a role in the complex trait of HCC susceptibility.
We identified five polymorphisms and interactions that contributed crucially to predicting HCC risk. These findings represented an important step towards improving HCC diagnosis and management.
揭示新的遗传标志物，有助于预测高加索人群的肝细胞癌（HCC）易感性。
本回顾性病例对照研究比较了 HCC 病例队列与两个独立的、无 HCC 的、年龄/性别匹配的对照组之间的基因型频率。HCC 队列包括 192 例接受原位肝移植的同质患者。第一个对照组包括 167 例与 HCC 队列相匹配的乙型肝炎（HBV）和/或丙型肝炎（HCV）感染百分比的患者。第二个对照组包括 192 例无病毒、健康的个体，用于评估鉴定的预测标志物的普遍性。所有病例和对照均为高加索人。这三个研究人群都用来自 21 个基因的 31 个标记物组成的面板进行了特征描述，这些基因编码与肝癌发生相关途径中的关键蛋白。研究终点是评估遗传变异与 HCC 发病之间的关联。
在感染 HBV/HCV 的高危患者中，有五个遗传标记被确定为 HCC 的危险因素。根据显性模型，三个多态性与降低 HCC 风险相关：rs3212986（OR=0.46，95%CI：0.30-0.71，=0.0005）、rs1138272（OR=0.41，95%CI：0.21-0.81，=0.0097）和 rs743572（OR=0.50，95%CI：0.31-0.79，=0.0032）。相反，根据隐性模型，两个多态性与增加 HCC 风险相关：rs1799794（OR=3.70，95%CI：1.02-13.39，=0.0461）和 rs1128503（OR=2.06，95%CI：1.18-3.61，=0.0111）。在根据病毒状态（HBV-或 HCV-阳性血清学）对患者进行分层的亚组分析中，这些关联仍然显著。两个变体表现出血清学特异性效应：rs1128503（OR=4.18，95%CI：1.55-11.29，=0.0048）在 HBV 阳性亚组中表现出效果；而 rs3212986（OR=0.33，95%CI：0.18-0.60，=0.0003）在 HCV 阳性亚组中表现出效果。在确定的五个标记物中，rs3212986（OR=0.43，<0.0001）和 rs743572（OR=0.73，=0.0310）在 HCC 患者与健康个体中的分布不同。通过递归分区方法，我们还证明了 rs3212986、rs743572、rs1138272 与先前描述的*3 预测标志物之间的显著基因-基因相互作用在 HCC 易感性的复杂特征中发挥了作用。
我们确定了五个有助于预测 HCC 风险的多态性和相互作用。这些发现代表了朝着改善 HCC 诊断和管理迈出的重要一步。
