Myeloperoxidase and superoxide dismutase 2 polymorphisms comodulate the risk of hepatocellular carcinoma and death in alcoholic cirrhosis #

Abstract

Alcohol increases reactive oxygen species (ROS) formation in hepatocyte mitochondria and by reduced nicotinamide adenine dinucleotide phosphate oxidases and myeloperoxidase (MPO) in Kupffer cells and liver-infiltrating neutrophils. Manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide, which, unless detoxified by glutathione peroxidase or catalase (CAT), can form the hydroxyl radical with iron. Our aim was to determine whether Ala16Val-superoxide dismutase 2 (SOD2), G-463A-MPO, or T-262C-CAT dimorphisms modulate the risks of hepatocellular carcinoma (HCC) and death in alcoholic cirrhosis. Genotypes and the hepatic iron score were assessed in 190 prospectively followed patients with alcoholic cirrhosis. During follow-up (61.1 ؎ 2.7 months), 51 patients developed HCC, and 71 died. The T-262C-CAT dimorphism did not modify hepatic iron, HCC, or death. The GG-MPO genotype did not modify iron but increased the risks of HCC and death. The hazard ratio (HR) was 4.7 (2.1-10.1) for HCC and 3.6 (1.9-6.7) for death. Carriage of one or two Ala-SOD2 allele(s) was associated with higher liver iron scores and higher risks of HCC and death. The 5-year incidence of HCC was 34.4% in patients with both the GG-MPO genotype and one or two Ala-SOD2 alleles, 5.1% in patients with only one of these two traits, and 0% in patients with none of these traits. Corresponding 5-year death rates were 37.6%, 11.6%, and 5%. Conclusion: The combination of the GG-MPO genotype (leading to high MPO expression) and at least one Ala-SOD2 allele (associated with high liver iron score) markedly increased the risks of HCC occurrence and death in patients with alcoholic cirrhosis.

Role of iron in hepatocellular carcinoma

“…16 In addition, it has been shown that patients with polymorphisms of oxidant/antioxidant enzymes were at increased risk of cancer. 17 Similarly, it has been reported that the risk of HCC is higher in patients who have nonalcoholic steatohepatitis (NASH)-related cirrhosis with hepatic iron excess. 18 However, the absence of a clear association in NAFLD between iron accumulation and HFE mutations means that there is no value in assessing risk of HCC in NASH-related cirrhosis by testing for HFE mutations.…”

PNPLA3 gene in liver diseases

“…These genetic traits are capable of modulating several biological pathways involved in hepatocarcinogenesis, such as inflammation [63,64], oxidative stress [65,66], and iron [67,68] or lipid metabolism [69]. In this setting, other genetic modifiers of lipid turnover seem to impact HCC risk in association with PNPLA3 genotype.…”

Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer

“…6 Miscoding of Ala to Val in SOD2 will result in SOD2 arresting in the inner mitochondrial membrane but not in the mitochondrial matrix, therefore reducing its functional activities. 6 Carriage of 1 or 2 Ala-SOD2 allele(s) reportedly has been associated with greater risks of hepatocellular carcinoma, 7 gastric cancer, 8 prostate cancer 9 and a poor prognosis in breast cancer. 10 The SNP in the GSTP1 gene (rs1695) is a substitution of A (isoleucine [Iso]) to G (valine [Val]) at position 105 that results in miscoded GSTP1 protein with decreased enzymatic activity and less effective detoxification.…”