Polymorphisms of a Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 and Aflatoxin B1-Related Hepatocellular Carcinoma
Polymorphisms of a Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 and Aflatoxin B1-Related Hepatocellular Carcinoma
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DOI：
10.1158/1055-9965.epi-15-0774
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发表时间：
2016-02-01
影响因子：
3.8
通讯作者：
Long, Xi-Dai
中科院分区：
文献类型：
--
作者：
Huang, Xiao-Ying;Yao, Jin-Guang;Long, Xi-Dai
背景：在肝细胞癌中观察到具有血小板反应蛋白基序的去整合素和金属蛋白酶5（ADAMTS 5）的表达改变。该基因的遗传多态性在黄曲霉毒素B1（AFB 1）相关的肝细胞癌尚未阐明。方法：我们进行了一项以医院为基础的病例对照研究，包括1,706例肝细胞癌病例和2,270例对照，没有任何肝脏疾病或肿瘤，以评估ADAMTS 5的74个多态性和AFB 1相关的肝细胞癌的风险和预后之间的关联。采用TaqMan-PCR或测序技术检测AFB 1暴露相关的基因型、mRNA水平和TP 53基因突变（TP 53 M）。结果：在74个基因多态性位点中，只有rs 2830581位点与肝癌风险有关。与rs 2830581 G等位基因纯合子（rs 2830581-GG）相比，rs 2830581 A等位基因（rs 2830581-GA或-AA）基因型增加了肝癌的风险（OR分别为1.85和4.40; 95% CI分别为1.57-2.19和3.43-5.64）。在联合效应分析中还观察到风险基因型和AFB 1暴露状态之间的显著交互效应。此外，rs 2830581多态性改变了患者的肿瘤无复发生存期和总生存期。该多态性不仅影响肝癌的病理特征，如肿瘤去分化和微血管密度，而且改变ADAMTS 5表达和肝动脉化疗栓塞治疗对肝癌的影响。结论：这些结果表明ADAMTS 5多态性可能是AFB 1相关肝癌的风险和预后生物标志物，rs 2830581是一个潜在的候选者。我们的研究结果支持ADAMTS 5 rs 2830581多态性改变AFB 1相关肝细胞癌风险和预后的假设。(C)2015年AACR。
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. (C) 2015 AACR.