Given that our Dabrafenib concentration several reported polymorphisms (including XPC codon 939, XPD codon 751, and GSTM1 polymorphisms) were also correlated with AFB1-related HCC risk, we analyzed the relative contribution of the XRCC4 rs28383151 polymorphism after adjusting for these three polymorphisms and observed

a similar risk value. These data suggest that the rs28383151 polymorphism should be an important genetic susceptible factor of cancer risk. In addition, we found some evidence of XRCC4-GSTM1 interactive effects on HCC risk, possibly because this gene-gene interaction results in a more-obvious accumulation of DNA damage and, consequently, correlates with a higher risk for HCC. To explore the possible

pathogenesis that the rs28383151 polymorphism increases AFB1-related HCC risk, we analyzed the effects of this polymorphism on XRCC4 expression and DNA repair function. We found that rs28383151 A alleles were significantly associated with down-regulated levels of XRCC4 expression, including protein and mRNA expression. Regarding the association between rs28383151 polymorphism and DNA repair capacity, we elucidated this association using the levels of AFB1 DNA adduct and the frequency of TP53M. This was done primarily because AFB1 DNA adducts are a major type of DNA damage induced by AFB1 exposure and corresponding levels are related not only to AFB1 exposure, but also to DNA repair capacity,2, 4 whereas TP53M is the characteristic genetic change correlated with AFB1 exposure, and MAPK inhibitor higher frequency of this mutation predicts higher AFB1 exposure and higher HCC risk.2, 16 This suggests that AFB1 DNA adducts and TP53M could be regarded as biomarkers of DNA repair function related to AFB1 exposure. Our results showed

上海皓元 that the rs28383151 polymorphism increased the level of AFB1 DNA adducts and frequency of TP53M. Together, these findings suggest that this polymorphism may decrease the DNA repair capacity of the NHEJ pathway through modulating XRCC4 expression levels and function. The DNA damage induced by AFB1 cannot be repaired effectively, with higher adduct levels leading to induction of mutations, such as in the p53 gene, and higher risk of hepatocellular carcinogenesis. Therefore, the rs28383151 polymorphism may play an important role in the carcinogenesis of Guangxiese HCC caused by AFB1. Another interesting finding of this study is that the rs28383151 polymorphism was associated with poor HCC prognosis, possibly because it correlates with the fact that this polymorphism increased the risk of PVT. Supporting our results, recent studies have shown that dysfunction of XRCC4 relates to tumor metastasis.