Moreover, mRNA levels of XRCC4 in cancerous tissues with rs28383151-GA or -AA were significantly lower than those with rs28383151-GG (Fig. 1C; P < 0.01). Together, these results suggest that this polymorphism should modify XRCC4 expression. Ganetespib ic50 To explore whether rs28383151 polymorphism effects DNA repair capacity, we analyzed the effects of a mutant type of rs28383151 polymorphism (XRCC4mt) on AFB1 DNA adducts

levels in AFB1-treated QSG-7701 cells with overexpression of XRCC4 (see Supporting Materials). We found that XRCC4mt had higher AFB1 DNA adducts levels (0.68 ± 0.05 nmol/μg DNA), compared to the WT of rs28383151 polymorphism (XRCC4wt, 0.44 ± 0.05 nmol/μg DNA, P < 0.01; Fig. 1D; Supporting Table 10). Because TP53M is the most important molecular signature of AFB1-induced HCC,16 we investigated whether this polymorphism modified this mutation in the 1,499 cancerous tissue subjects. Results showed that risk genotypes of XRCC4 increased the frequency of TP53M (Fig. 1E), and corresponding risk values were 1.60 and 3.92 for rs28383151-GA and rs28383151-AA, respectively (Table 3). Taken together, these findings suggest that the rs28383151 polymorphism

might correlate with DNA repair capacity for repair of DNA damage caused by AFB1 exposure. To assess the clinical relevance of rs28383151 polymorphism, we analyzed the survival follow-up information of all HCC patients. Among these subjects, 1,092 without decompensated cirrhosis received the same curative resection treatment, according to Chinese Manage Criteria of HCC,17 and were included for final survival analysis. Association PLK inhibitor analysis between risk genotypes (namely, genotypes with rs28383151 A alleles; rs28383151-GA/AA) or nonrisk genotype (rs28383151-GG) and the clinic-pathologic characteristics

of HCC were first performed separately (Supporting Table MCE公司 11). We observed a significant distribution difference of genotypes among different AFB1 exposure levels, tumor size, and recurrence status, but not in AFB1 exposure years, gender, minority, HBsAg, cirrhosis, or TNM stage (Supporting Table 11). Survival analysis next showed that HCC cases carrying rs28383151-GA/AA, compared with those with rs28383151-GG, had shorter RFS (median RFS time [MRT] was 16 versus 33 months; Fig. 2A) and higher recurring risk (Table 4), particularly under high AFB1 exposure conditions (Fig. 2A). Additionally, this polymorphism was related to the OS of HCC cases (Fig. 2B), and some evidence of multiplicative interaction was found for rs28383151 polymorphism and AFB1 exposure (Pinteraction < 0.05; Table 4). On the basis of a recent report showing that the dysregulation of XRCC4 is related to tumor metastasis,18 we investigated whether the rs28383151 polymorphism influenced the risk of PVT, the most common metastasis type of HCC,19, 20 in 1,092 HCC cases during follow-up after curative treatment (Table5). Results exhibited that rs28383151 A alleles significantly increased PVT risk (OR = 2.26; P = 3.94 × 10−5).