黄曲霉毒素B1暴露及乙型肝炎病毒感染与肝细胞癌中TP53基因R249S突变的全基因组关联研究
Genome-wide association study of the TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and infection with hepatitis B virus.
作者信息
Han Chuangye, Yu Tingdong, Qin Wei, Liao Xiwen, Huang Jianlu, Liu Zhengtao, Yu Long, Liu Xiaoguang, Chen Zhiwei, Yang Chengkun, Wang Xiangkun, Mo Shutian, Zhu Guangzhi, Su Hao, Li Jiaquan, Qin Xue, Gui Ying, Mo Zengnan, Li Lequn, Peng Tao
机构信息
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.
School of Basic Medical Sciences, Guangxi Medical University, Nanning, China.
出版信息
J Gastrointest Oncol. 2020 Dec;11(6):1333-1349. doi: 10.21037/jgo-20-510.
BACKGROUND
Exposure to dietary aflatoxin B1 (AFB1) induces DNA damage and mutation in the TP53 gene at codon 249, known as the TP53 R249S mutation, and is a major risk factor for hepatocellular carcinoma (HCC). AFB1 and the hepatitis B virus (HBV) together exert synergistic effects that promote carcinogenesis and TP53 R249S mutation in HCC.
METHODS
A genome-wide association study (GWAS) of whole genome exons was conducted using 485 HCC patients with chronic HBV infection. This was followed by an independent replication study conducted using 270 patients with chronic HBV infection. Immunohistochemistry was used to evaluate TP53 expression in all samples. This showed a correlation between codon 249 mutations and TP53 expression. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both the GWAS and replication study. The associations between identified variants and the expression levels of their located genes were analyzed in 20 paired independent samples.
RESULTS
The likelihood of positive TP53 expression was found to be higher in HCC patients with the R249S mutation both in the GWAS (P<0.001) and the replication study (P=0.006). The combined analyses showed that the TP53 R249S mutation was significantly associated with three single nucleotide polymorphisms (SNPs): ADAMTS18 rs9930984 (adjusted P=4.84×10), WDR49 rs75218075 (adjusted P=7.36×10), and SLC8A3 rs8022091 (adjusted P=0.042). The TP53 R249S mutation was found to be highly associated with the TT genotypes of rs9930984 (additive model, P=0.01; dominant model, P=6.43×10) and rs75218075 (additive model, P=0.002; dominant model, P=2.16×10). Additionally, ADAMTS18 mRNA expression was significantly higher in HCC tissue compared with its expression in paired non-tumor tissue (P=0.041), and patients carrying the TT genotype at rs9930984 showed lower ADAMTS18 expression in non-tumor tissue compared with patients carrying the GT genotype (P=0.0028). WDR49 expression was markedly lower in HCC tissue compared with paired non-tumor tissue (P=0.0011).
CONCLUSIONS
TP53 expression is significantly associated with the R249S mutation in HCC. Our collective results suggest that rs9930984, rs75218075, and rs8022091 are associated with R249S mutation susceptibility in HCC patients exposed to AFB1 and HBV infection.
背景
膳食黄曲霉毒素B1（AFB1）暴露会诱导第249密码子处TP53基因的DNA损伤和突变，即TP53 R249S突变，是肝细胞癌（HCC）的主要危险因素。AFB1与乙型肝炎病毒（HBV）共同发挥协同作用，促进HCC的致癌作用和TP53 R249S突变。
方法
对485例慢性HBV感染的HCC患者进行全基因组外显子的全基因组关联研究（GWAS）。随后使用270例慢性HBV感染患者进行独立重复研究。采用免疫组织化学法评估所有样本中TP53的表达。结果显示第249密码子突变与TP53表达之间存在相关性。基于GWAS和重复研究确定了HCC中TP53 R249S突变的易感变异。在20对独立样本中分析了所确定变异与其所在基因表达水平之间的关联。
结果
在GWAS（P<0.001）和重复研究（P=0.006）中，发现R249S突变的HCC患者中TP53阳性表达的可能性更高。综合分析表明，TP53 R249S突变与三个单核苷酸多态性（SNP）显著相关：ADAMTS18 rs9930984（校正P=4.84×10）、WDR49 rs75218075（校正P=7.36×10）和SLC8A3 rs8022091（校正P=0.042）。发现TP53 R249S突变与rs9930984（加性模型，P=0.01；显性模型，P=6.43×10）和rs75218075（加性模型，P=0.002；显性模型，P=2.16×10）的TT基因型高度相关。此外，与配对的非肿瘤组织相比，HCC组织中ADAMTS18 mRNA表达显著更高（P=0.041），rs9930984处携带TT基因型的患者与携带GT基因型的患者相比，非肿瘤组织中ADAMTS18表达更低（P=0.0028）。与配对的非肿瘤组织相比，HCC组织中WDR49表达明显更低（P=0.0011）。
结论
HCC中TP53表达与R249S突变显著相关。我们的综合结果表明，rs9930984、rs75218075和rs8022091与暴露于AFB1和HBV感染的HCC患者的R249S突变易感性相关。
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