BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease

Abstract

The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the BRIP1 locus reached array-wide significance (Chi-squared SV-Perm, P=5.00×10^-4) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The BRIP1 haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The BRIP1 'AAA' haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19-3.39); false discovery rate (FDR)-P=1.31×10^-2]. In the Derivation#2 study, results were confirmed for the BRIP1 'GGG' haplotype [OR, 0.53 (0.36-0.79); FDR-P=3.90×10^-3]. In both Validation#1 and #2 studies, BRIP1 'AAA' haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09-2.68); FDR-P=7.30×10^-2; and OR, 6.45 (4.17-9.99); FDR-P=2.33×10^-19, respectively]. Association between the BRIP1 locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease.

Keywords: BRIP1; DNA repair genes; hepatitis B virus; hepatitis C virus; hepatocellular carcinoma.

Figure 1

A. Overview on the study design; B. Manhattan plot reporting the association between haplotype blocks on DNA repair genes and hepatocellular carcinoma risk in the Derivation #1 study among patients with viral cirrhosis. Association results of the single-variant analysis (−Log10 P) are plotted against genomic position (GRCh37 hg19); C. Forest plots showing the effect size of associations between HHC risk and BRIP1 haplotypes in derivation (Derivation #1 and #2) and validation (Validations #1 and #2) studies among patients with viral hepatitis. For each analysis, the odds ratio of the association is reported with the 95% confidence interval (solid line) [EUR: Europeans; AFR: Africans; HCC: hepatocellular carcinoma; HBV: hepatitis B virus; HCV: hepatitis C virus; Derivation #1: HCC patients from the CiRCE study (n=56) were compared with HBV- and/or HCV-induced cirrhosis but without HCC from the CiRCE study (n=85); Derivation #2: HCC patients from the CiRCE study (n=56) were compared with patients with HCV-related chronic liver disease from two European cohorts (ANRS Genoscan study group, n=398; Swiss Hepatitis C Cohort Study, n=572); Validation #1: HCC patients from the Jean Verdier Hospital cohort (n=136) were compared with HCC-free cirrhotic patients (Jean Verdier Hospital cohort) (n=99); Validation #2: HCC patients from the Jean Verdier Hospital cohort (n=136) were compared with HBV- and/or HCV-infection from the Benin-Togo cohort (n=305)].

Figure 2. Cumulative probability of hepatocellular carcinoma occurrence among patients with viral cirrhosis in the CiRCE study according to BRIP1 variants

Cumulative probability of hepatocellular carcinoma occurrence according to BRIP1 variants [rs4986763 (A), rs4986764 (B), and rs4986765 (C)] among patients with viral cirrhosis using multivariate Cox proportional-hazards regression analysis; GG: Major homozygous genotype, GA: Heterozygous genotype, AA: Minor homozygous genotype; (D) Structure of the BRIP1 gene. The BRIP1 gene codes for the BRIP1 protein which comprises DNA Helicase domains (0, I, Ia, II, III, IV, V, and VI), a BLM binding domain, and MRE11 binding domain. Genomic positions of the three BRIP1 variants found in association with hepatocellular cancer risk among patients with viral cirrhosis are indicated (adapted from references [24, 27, 58]).