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The effects of TACE treatment on the survival of HCC patients. Multiple cox regression analysis (including all known risk factors of Guangxiese HCC) was used to analysis the relative death risk and tumor reoccurrence risk for these cases accepting TACE treatment. (A-B) The survival analysis based on all 1299 HCC cases. (C-D) The survival analysis based on these HCC cases with ADAMTS5 rs2830581-AA. (E-F) The survival analysis based on these HCC cases with ADAMTS5 rs2830581-GA. (G-H) The survival analysis based on these HCC cases with ADAMTS5 rs2830581-GG.

Background: Altered expression of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is observed in hepatocellular carcinoma. The genetic polymorphisms of this gene in aflatoxin B1 (AFB1)–related hepatocellular carcinoma have not yet been elucidated.Methods: We conducted a hospital-based case–control study, including 1,706 hepatocellular carcinoma cases and 2,270 controls without any liver diseases or tumors, to assess the association between 74 polymorphisms in ADAMTS5 and AFB1-related hepatocellular carcinoma risk and prognosis. Genotype, mRNA levels, and TP53 gene mutation (TP53M) related to AFB1 exposure were tested using TaqMan-PCR or sequencing technique. ADAMTS5 protein level and microvessel density were analyzed by IHC.Results: Among these 74 polymorphisms, only rs2830581 affected hepatocellular carcinoma risk. Compared with the homozygote of rs2830581 G alleles (rs2830581-GG), the genotypes of rs2830581 A alleles (rs2830581-GA or -AA) increased hepatocellular carcinoma risk (OR: 1.85 and 4.40; 95% CI: 1.57–2.19 and 3.43–5.64, respectively). Significant interactive effects between risk genotypes and AFB1 exposure status were also observed in the joint effects analysis. Furthermore, the rs2830581 polymorphism modified the tumor recurrence-free survival and overall survival of patients. This polymorphism not only affected pathologic features of hepatocellular carcinoma such as tumor dedifferentiation and microvessel density, but also modified ADAMTS5 expression and the effects of transarterial chemoembolization treatment on hepatocellular carcinoma.Conclusions: These results suggest ADAMTS5 polymorphisms may be risk and prognostic biomarkers of AFB1-related hepatocellular carcinoma, and rs2830581 is a potential candidate.Impact: Our findings support the hypothesis that ADAMTS5 rs2830581 polymorphism modifies AFB1-related hepatocellular carcinoma risk and prognosis. Cancer Epidemiol Biomarkers Prev; 25(2); 334–43. ©2015 AACR.

Supplementary Table S1 The polymorphisms information of ADAMTS5 and genotyping analysis. Supplementary Table S2 Demographic and Etiologic Characteristics of HCC Cases and Controls. Supplementary Table S3 Hardy-Weinberg equilibrium (HWE) test for ADAMTS5 genotypes among controls. Supplementary Table S4 ADAMTS5 polymorphisms and HCC risk. Supplementary Table S5 ADAMTS5 rs2830581 polymorphism and HCC risk stratified by matching factors (HBV and HCV infection, age, gender, and race). Supplementary Table S6. ADAMTS5 Polymorphism and Expression Levels of ADAMTS5 Protein. Supplementary Table S7 The ADAMTS5 rs2830581 polymorphism and the clinic-pathological features of HCC. Supplementary Table S8 The clinic-pathological features of HCC cases with or without TACE treat.

Supplementary Materials and Methods

Supplementary Figure Legends