Liver, Pancreas and Biliary TractPNPLA3 rs738409 and TM6SF2 rs58542926 variants increase the risk of hepatocellular carcinoma in alcoholic cirrhosis
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third cause of cancer-related mortality worldwide [1]. The majority of HCCs develop in patients with liver cirrhosis in Western countries with an incidence ranging from 1 to 8% annually. The aetiology of liver cirrhosis complicated with the occurrence of HCC is predominantly related to chronic viral infection (hepatitis B or hepatitis C) or alcohol consumption [2]. A growing incidence of HCC was reported in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH) [3]. Male gender and older age are also the main demographic independent predictors of HCC development in cirrhosis [4]. Inherited factors were implicated in the pathogenesis of HCC, and these factors contribute to the greater inter-individual variability in disease susceptibility [5].
Genome-wide association studies failed to identify a single genetic pattern that accounts for hepato-carcinogenesis in cirrhosis, but several reports demonstrated a strong association between the presence of 148 methionine variants of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and the occurrence of HCC, particularly in patients with alcoholic or NASH-related liver cirrhosis [6], [7], [8]. PNPLA3 encodes a protein that is distributed between liver lipid droplets and membranes, and it exhibits a predominantly hydrolase activity [9], [10]. The effect of the 148 methionine (rs738409 G) variant on loss or gain of function remains controversial despite numerous studies on PNPLA3 enzymatic activity. The link between PNPLA3 variants and liver lipid-related diseases is strong, and this link is no longer questionable. However, a simple mechanism that involves the increase in fatty acid formation and/or impairment of fatty acid depletion is not known. The PNPLA3 148Met variant favours hepatocellular fat accumulation in the presence of triggering factors, such as obesity, alcohol consumption and insulin resistance, which leads to liver fibrosis progression and HCC development. A direct carcinogenic effect of the PNPLA3 148Met variant was proposed [11], but the vast majority of the available data suggest that this variant enhances HCC susceptibility in patients with established liver cirrhosis [6].
The transmembrane 6 superfamily 2 (TM6SF2) is the putative functional gene in the 19p12 locus that is responsible for lipid metabolism in the liver [12], [13], [14]. TM6SF2 encodes a protein of 351 amino acids with 7–10 predicted transmembrane domains, and it is predominantly expressed in the liver and intestine. TM6SF2 siRNA inhibition is associated with a reduced secretion of triglyceride-rich lipoproteins and increased cellular triglyceride concentrations and lipid droplet content, and TM6SF2 overexpression is associated with reduced liver cell steatosis. The genetic variant encoding Glu167Lys (rs58542926 C>T) is associated with decreased protein expression, which contributes to the enhancement of liver triglyceride content and NAFLD development [14].
These data suggest that both genetic variants strongly influence lipid metabolism in the liver and favour the development of steatosis. This aspect highlights recent observations of the strict relationship between lipid accumulation in the liver and the risk of fibrosis progression and cancer development. Therefore, a synergistic or complementary effect of PNPLA3 and TM6SF2 genetic variants in modifying the risk of HCC development in patients with liver cirrhosis may be hypothesized. This effect may also occur in patients in whom steatosis progresses to cirrhosis, which originated from alcohol-related liver damage. This hypothesis has not been carefully investigated.
This study assessed the role of PNPLA3 rs738409 and TM6SF2 rs58542926 genetic variants in the conditioning of HCC development in patients with alcoholic- compared to viral-related liver cirrhosis.
Section snippets
Patients
The study included 511 Italian patients of Caucasian ethnicity who were diagnosed with cirrhosis. Most patients (N = 294, 57.5%) received transplantation for end-stage liver disease. Histological evaluation of the explanted liver confirmed the diagnoses of liver cirrhosis and HCC in this first group. Cirrhosis was diagnosed clinically in the remaining patients (N = 217, 42.5%), who were not referred for transplantation, based on signs of portal hypertension, pertinent imaging features and
TM6SF2 rs58542926 C>T and PNPLA3 rs738409 C>G genotypes
No significant departure from Hardy–Weinberg equation was observed for either polymorphism: PNPLA3 rs738409 C>G: controls p = 0.461, viral cirrhosis p = 0.738 and alcoholic cirrhosis p = 0.213; TM6SF2 rs58542926 C>T: controls p = 0.381, viral cirrhosis p = 0.348 and alcoholic cirrhosis p = 0.850.
Genetic polymorphisms and the aetiology of liver cirrhosis
Table 2 presents allele and genotype frequencies for both genetic polymorphisms in patients with viral (hepatitis B or hepatitis C, N = 285) and alcoholic (N = 226) liver cirrhosis compared to controls, adjusting the
Discussion
Several large-scale epidemiological studies stressed that overweight and obesity result in a substantial increase in cancer risk [21], [22], [23]. Similarly, a recent meta-analysis noted that the relative risk of liver cancer was 117% for overweight subjects and 189% for obese subjects [24]. Obesity, particularly central obesity, is highly predictive of hepatic steatosis and liver disease progression [25], [26]. Fatty liver is also strongly associated with alcohol consumption. Alcoholic fatty
Conflict of interest
None declared.
References (40)
- et al.
Hepatocellular carcinoma
Lancet
(2012) - et al.
Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis
Journal of Hepatology
(2012) - et al.
Carriage of the PNPLA3 rs738409 C>G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma
Journal of Hepatology
(2014) - et al.
Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities
Journal of Biological Chemistry
(2004) - et al.
A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis
Journal of Biological Chemistry
(2010) - et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
American Journal of Human Genetics
(2007) - et al.
BOOST: a fast approach to detecting gene–gene interactions in genome-wide case-control studies
American Journal of Human Genetics
(2010) - et al.
Overweight, obesity, and cancer risk
Lancet Oncology
(2002) - et al.
Prevalence of the TM6SF2 variant and non-alcoholic fatty liver disease in Chinese
Journal of Hepatology
(2014) - et al.
A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease
Journal of Hepatology
(2014)