A multicenter matched case-control analysis on seven polymorphisms from HMGB1 and RAGE genes in predicting hepatocellular carcinoma risk

Abstract

Based on 540 hepatocellular carcinoma patients and 540 age- and gender-matched controls, we tested the hypothesis that high mobility group protein box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) genes are two potential candidate susceptibility genes for hepatocellular carcinoma in a multicenter hospital-based case-control analysis. The genotypes of seven widely-studied polymorphisms were determined, and their distributions respected the Hardy-Weinberg equilibrium. The mutant alleles of two polymorphisms, rs1045411 in HMGB1 gene and rs2070600 in RAGE gene, had significantly higher frequencies in patients than in controls (P < 0.001), with the power to detect this significance of being over 99.9%. Moreover, the above two polymorphisms increased the risk of developing hepatocellular carcinoma significantly, particularly for rs2070600 under the additive (odds ratio [OR] = 1.77; 95% confidence interval [CI]: 1.34-2.32; P < 0.001) and dominant (OR = 1.75; 95% CI: 1.23-2.50; P = 0.002) models after adjusting for body mass index, smoking and drinking. Haplotype analysis showed that the T-C-T haplotype (rs1045411-rs2249825-rs1415125) in HMGB1 gene was associated with a 2.47-fold (95% CI: 1.41-4.34; P = 0.002) increased risk of hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment. In RAGE gene, the T-T-A-G (rs1800625-rs1800624-rs2070600-rs184003) (adjusted OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (adjusted OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma compared with the commonest T-T-G-G haplotype. In summary, we identified two risk-associated polymorphisms (rs1045411 and rs2070600), and more importantly a joint impact of seven polymorphisms from the HMGB1/RAGE axis in susceptibility to hepatocellular carcinoma.

Association of Polymorphism rs1045411 in the HMGB1 Gene with Cancer Risk: Evidence from a Meta-analysis

“…Sensitivity analysis was performed by removing one study at a time to assess the stability of these results. After the removal of Wang et al study 25 , the resulting heterogeneity across studies decreased from moderate heterogeneity ( χ2 = 17.31; df = 8; p =0.03; I 2 = 54%) to low ( χ2 = 7.14; df = 7; p =0.41; I 2 = 2%) in the dominant model (TT vs. CC+TC). However, after eliminating the Wang et al study 25 , the pooled ORs were not distinctly changed, with stable results.…”

“…After the removal of Wang et al study 25 , the resulting heterogeneity across studies decreased from moderate heterogeneity ( χ2 = 17.31; df = 8; p =0.03; I 2 = 54%) to low ( χ2 = 7.14; df = 7; p =0.41; I 2 = 2%) in the dominant model (TT vs. CC+TC). However, after eliminating the Wang et al study 25 , the pooled ORs were not distinctly changed, with stable results. Funnel plots were drawn to determine the risk of bias, and they were symmetric (Figure 5 ), indicating the absence of publication bias.…”

“…During the past few years, some studies have reported the association between HMGB1 polymorphisms (rs2249825, rs1045411, rs1412125 and rs1360485) and different cancer types 25 . After reviewing lots of literatures on HMGB1 polymorphisms, a great deal of literature and information indicate that the HMGB1 rs1045411 polymorphism might be most likely associated with increased cancer risk, though the results are controversial.…”

“…HMGB1 is a tumour-related gene 28 , and its overexpression of HMGB1 is associated with the hallmarks of cancer 29 , such as unlimited replicative potential, ability to develop blood vessels, evasion of programmed cell death, self-sufficiency in growth signals, insensitivity to inhibitors of growth, inflammation, tissue invasion and metastasis 30 . Because the HMGB1 rs1045411 polymorphism is closely correlated with altered binding of miR-505-5P in the 3'-UTR of mRNA transcripts, HMGB1 gene polymorphisms could emerge as a crucial player in cancer development through a post-transcriptional mechanism 7 , 25 . Furthermore, since the rs1045411 polymorphism resides in the 3'-flanking regions, suggesting a role in mRNA stability as miRNAs can bind the 3'-UTR regions of mRNA transcripts and inhibit HMGB1 expression at the post-transcriptional level 25 .…”

The Impact of HMGB1 Polymorphisms on Prostate Cancer Progression and Clinicopathological Characteristics

“…Moreover, HMGB1 was suggested as a novel target for potential therapeutics since highly expressed HMGB1 was found to be associated with the epithelial-to-mesenchymal transition (EMT) and the overexpression of MMP-1, MMP-3, and MMP-10 via the RAGE/NF-κB signaling pathways, facilitating prostate cancer metastasis [ 1 , 16 , 17 , 18 , 19 , 20 ]. Furthermore, polymorphisms of HMGB1 have been associated with many cancers, including oral squamous cell carcinoma (OSCC) [ 21 , 22 ], lung cancer [ 23 , 24 , 25 , 26 ], breast cancer [ 27 , 28 , 29 ], gastric cancer [ 30 ], hepatocellular carcinoma (HCC) [ 31 , 32 ], and colorectal cancer (CRC) [ 33 ], and it was suggested that the SNPs of HMGB1 may provide a potential biomarker for predicting cancer risk, tumor development, or chemotherapy responses [ 21 , 25 , 27 , 31 ]. However, the impact of HMGB1 polymorphisms on prostate cancer susceptibility and clinicopathologic characteristics has remained uninvestigated.…”