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.
Highlights
Hepatocellular carcinoma (HCC) is the commonest primary malignant tumor of the liver
Among the 253 haplotype blocks tested for their association with hepatocellular carcinoma (HCC) risk only one reached array-wide significance and was located in the BRIP1 locus (BRCA1 interacting protein C-terminal helicase 1; Gene ID: 83990; formerly known as BACH1 or FANCJ) in the chromosome 17q23 (Chi-Squared SV Perm, P=5.00×10−4) (See Supplemental Table S3 in the supplementary appendix)
Among the three different haplotypes of the BRIP1 haplotype block, the ‘AAA’ haplotype was associated with an increased risk of HCC (EM frequency in cases, 38%; EM frequency in controls, 24%; odds ratio, 2.01; 95% confidence intervals (95% CI), 1.19 to 3.39; P=8.74×10−3; false discovery rate (FDR)-P=1.31×10−2)
Summary
Hepatocellular carcinoma (HCC) is the commonest primary malignant tumor of the liver. It is the fifth most common cancer in men and the seventh in women, and it ranks third in annual cancer mortality rates worldwide [1, 2]. HCC risk factors induce malignant transformation of hepatocytes by increasing cellular turnover leading to multiple genetic alterations such as chromosomal instability with point mutations and deletions causing the activation or inactivation of protooncogenes or tumor suppressor genes, respectively [5]. HCV- and HBV-related HCC develop in an environment of ongoing inflammation and cell injury, both leading to increased cell turnover and liver fibrosis [6]. The pathogenesis of HCC associated with alcoholic cirrhosis follows other mechanistic pathways that mainly involve oxidative stress in relation with ethanol metabolism and inflammation [9]
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