含血小板反应蛋白基序的解聚素和金属蛋白酶5多态性与黄曲霉毒素B1相关肝细胞癌

Polymorphisms of a Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 and Aflatoxin B1-Related Hepatocellular Carcinoma.

作者信息

Huang Xiao-Ying, Yao Jin-Guang, Huang Bing-Chen, Ma Yun, Xia Qiang, Long Xi-Dai

机构信息

Department of Pathology, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China.

Department of Pathology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China.

出版信息

Cancer Epidemiol Biomarkers Prev. 2016 Feb;25(2):334-43. doi: 10.1158/1055-9965.EPI-15-0774. Epub 2015 Dec 16.

DOI:10.1158/1055-9965.EPI-15-0774

PMID:26677209

Abstract

BACKGROUND

Altered expression of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is observed in hepatocellular carcinoma. The genetic polymorphisms of this gene in aflatoxin B1 (AFB1)-related hepatocellular carcinoma have not yet been elucidated.

METHODS

We conducted a hospital-based case-control study, including 1,706 hepatocellular carcinoma cases and 2,270 controls without any liver diseases or tumors, to assess the association between 74 polymorphisms in ADAMTS5 and AFB1-related hepatocellular carcinoma risk and prognosis. Genotype, mRNA levels, and TP53 gene mutation (TP53M) related to AFB1 exposure were tested using TaqMan-PCR or sequencing technique. ADAMTS5 protein level and microvessel density were analyzed by IHC.

RESULTS

Among these 74 polymorphisms, only rs2830581 affected hepatocellular carcinoma risk. Compared with the homozygote of rs2830581 G alleles (rs2830581-GG), the genotypes of rs2830581 A alleles (rs2830581-GA or -AA) increased hepatocellular carcinoma risk (OR: 1.85 and 4.40; 95% CI: 1.57-2.19 and 3.43-5.64, respectively). Significant interactive effects between risk genotypes and AFB1 exposure status were also observed in the joint effects analysis. Furthermore, the rs2830581 polymorphism modified the tumor recurrence-free survival and overall survival of patients. This polymorphism not only affected pathologic features of hepatocellular carcinoma such as tumor dedifferentiation and microvessel density, but also modified ADAMTS5 expression and the effects of transarterial chemoembolization treatment on hepatocellular carcinoma.

CONCLUSIONS

These results suggest ADAMTS5 polymorphisms may be risk and prognostic biomarkers of AFB1-related hepatocellular carcinoma, and rs2830581 is a potential candidate.

IMPACT

Our findings support the hypothesis that ADAMTS5 rs2830581 polymorphism modifies AFB1-related hepatocellular carcinoma risk and prognosis.

摘要

背景

在肝细胞癌中观察到含血小板反应蛋白基序的解聚素和金属蛋白酶5（ADAMTS5）表达改变。该基因在黄曲霉毒素B1（AFB1）相关肝细胞癌中的基因多态性尚未阐明。

方法

我们开展了一项基于医院的病例对照研究，纳入1706例肝细胞癌病例和2270例无任何肝脏疾病或肿瘤的对照，以评估ADAMTS5基因中74个多态性与AFB1相关肝细胞癌风险及预后之间的关联。使用TaqMan-PCR或测序技术检测与AFB1暴露相关的基因型、mRNA水平和TP53基因突变（TP53M）。通过免疫组化分析ADAMTS5蛋白水平和微血管密度。

结果

在这74个多态性中，只有rs2830581影响肝细胞癌风险。与rs2830581 G等位基因纯合子（rs2830581-GG）相比，rs2830581 A等位基因（rs2830581-GA或-AA）的基因型增加了肝细胞癌风险（OR：1.85和4.40；95% CI：分别为1.57 - 2.19和3.43 - 5.64）。在联合效应分析中也观察到风险基因型与AFB1暴露状态之间存在显著的交互作用。此外，rs2830581多态性改变了患者的无瘤复发生存期和总生存期。这种多态性不仅影响肝细胞癌的病理特征，如肿瘤去分化和微血管密度，还改变了ADAMTS5的表达以及经动脉化疗栓塞治疗对肝细胞癌的疗效。