BRIP1coding 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.

Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma

“…Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver ( El-Serag, 2011 ; Bruix et al, 2016 ; Oussalah et al, 2016 ). It is the fifth most common cancer in men and the seventh in women, and ranks second in annual cancer mortality rates worldwide, with liver cancer diagnosed in >700,000 people annually ( El-Serag, 2011 ; Bruix et al, 2016 ; World Health Organization, 2017 ).…”

Plasma mSEPT9: A novel circulating cell-free DNA-based epigenetic biomarker to diagnose hepatocellular carcinoma

“…Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver (El-Serag, 2011;Bruix et al, 2016;Oussalah et al, 2016). It is the fifth most common cancer in men and the seventh in women, and ranks second in annual cancer mortality rates worldwide, with liver cancer diagnosed in N700,000 people annually (ElSerag, 2011;Bruix et al, 2016;World Health Organization, 2017).…”

The repair gene <em>BACH1</em> - a potential oncogene

“… 19 Mutations in BACH1 also lead to liver carcinogenesis, among patients with viral cirrhosis, due to impaired DNA mismatch repair pathway. 20 In summary to the above lines, the mutated version of BACH1 gene leads to the development of oncogenicity ( Figure 1 ).…”

“…Mutational analysis reveals that the BRIP1 locus is strongly associated with hepatocellular carcinoma (HCC) risk in patients with hepatitis B virus (HBV) and/or hepatitis C virus (HCV)-induced liver disease. 20 The variants of BACH1 which are linked with viral cirrhosis have mutations in the domains which interacts with the DSB repair protein or DNA mismatch repair protein like MRE11 or MUTL α ( Figure 2 ) [ 20 ]. Alternately, mutations in the mismatch repair proteins like MLH1 and MSH2, which regulate the localization of BACH1 at the DSBs has been recognized as bladder cancer driver genes.…”