Background/Aims: Dietary aflatoxin B1 (AFB1) exposure, which induces DNA damage and codon 249 mutation of the TP53 gene, is one of the major risk factors for hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) infection and AFB1 exert synergistic effects to promote carcinogenesis and TP53 R249S mutation in HCC. Methods: A genome-wide association study (GWAS) was conducted on 485 cases of HCC with chronic HBV infection, followed by a two-stage replication study on 270 cases with chronic HBV infection. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both GWAS and replication analysis. The associations of identified variants with expression levels of their located genes were validated in 20 paired independent samples. Results: Our results showed that TP53 R249S was significantly associated with ADAMTS18 rs9930984 (adjusted P = 4.84 x 10⁻⁶), WDR49 rs75218075 (adjusted P = 7.36 x 10⁻⁵) and SLC8A3 rs8022091 (adjusted P = 0.042). Additionally, ADAMTS18 mRNA expression was significantly higher in HCC tissue, compared with 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 those carrying the GT genotype (P = 0.0028). Conclusions: TP53 expression is significantly associated with R249S mutation in HCC. Our collective results suggest that rs9930984, rs75218075 and rs8022091 are associated with susceptibility to the R249S mutation in cases of HCC exposed to AFB1 and HBV infection.

中文翻译：

---

全基因组肝细胞癌中TP53 R249S突变与黄曲霉毒素B1暴露和乙型肝炎病毒感染的关联研究

背景/目的：饮食中的黄曲霉毒素B1（AFB1）暴露可引起TP53基因的DNA损伤和249位密码子突变，是导致肝细胞癌（HCC）的主要危险因素之一。乙型肝炎病毒（HBV）感染和AFB1发挥协同作用，促进肝癌的致癌作用和TP53 R249S突变。方法：对485例慢性HBV感染的HCC患者进行了全基因组关联研究（GWAS），然后对270例慢性HBV感染的患者进行了两阶段复制研究。基于GWAS和复制分析，确定了HCC中TP53 R249S突变的易感性变异。在20个配对的独立样本中验证了已鉴定变体与它们所定位基因的表达水平的关联。结果：P = 4.84 x 10 ^-6），WDR49 rs75218075（调整后的P = 7.36 x 10 ^-5）和SLC8A3 rs8022091（调整后的P = 0.042）。此外，与成对的非肿瘤组织相比，HCC组织中ADAMTS18 mRNA的表达显着更高（P = 0.041），并且在rs9930984携带TT基因型的患者与携带GT基因型的患者相比，在非肿瘤组织中的ADAMTS18表达更低（P = 0.0028）。结论：TP53表达与肝癌R249S突变显着相关。我们的集体结果表明，在暴露于AFB1和HBV感染的HCC病例中，rs9930984，rs75218075和rs8022091与R249S突变的易感性相关。