The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409 [G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model 5 1.77; 95% confidence interval [CI]: 1.42-2.19; P 5 2.78 3 10 27 ). This association was more pronounced in ALD (OR 5 2.20; 95% CI: 1.80-2.67; P 5 4.71 3 10 215 ) than in CHC patients (OR 5 1.55; 95% CI: 1.03-2.34; P 5 3.52 3 10 22 ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development. (HEPATOLOGY 2014;59:2170-2177

Background: Epidemiological studies emphasize the possible role of persistent organic pollutants (POPs) in obesity and the metabolic syndrome. These pollutants are stored in adipose tissue (AT).Objectives: Our aim was to study the effects of POPs on human adipose cells and rodent AT.Methods: Using human multipotent adipose-derived stem cells, we carried out large-scale gene expression analysis to identify the major pathways modified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyl (PCB) congener 126 (PCB-126), and PCB-153 and to evaluate their toxic effects. The effects of TCDD on gene expression and AT histology were also assessed in mice.Results: The most significantly regulated genes in both precursor cells and adipocytes were those involved in the inflammatory/immune response, cancer, and metabolism pathways. Interestingly, the fold induction and the number of modulated genes were higher in precursors than in adipocytes, suggesting that the former could be more sensitive to the effect of pollutants. When cells were treated with combinations of pollutants, the effects of the AhR ligands TCDD and PCB-126 were dominant compared with those of the non-dioxin-like PCB-153. The effects of AhR ligands were reduced by the AhR antagonist α-naphthoflavone. The regulation of inflammatory pathway was observed in wild-type AT but not in AhR-knockout mice.Conclusions: Both in vitro and in vivo studies showed that adipose cells were targets of AhR ligands and suggest that inflammation is one of the main regulated pathways. These observations suggest a possible contribution of pollutants to low-grade AT inflammation that accompanies the pathogenesis of metabolic diseases.

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Recently, a loss of function variant (rs72613567) in 17‐beta‐hydroxysteroid dehydrogenase 13 (HSD17B13) has been identified as protective of nonalcoholic (NAFLD) and alcoholic liver disease (ALD). However, the role of this single‐nucleotide polymorphism (SNP) in the development of hepatocellular carcinoma (HCC) is currently unknown. A total of 3,315 European patients with HCC (n = 1,109) or without HCC, but with chronic liver disease (CLD; n = 2,206), from four centers were analyzed either by whole‐exome sequencing (WES; exploratory cohort, 285 HCC) or genotyped for HSD17B13 rs72613567 (validation cohort, 824 HCC and all CLD). We included a control group of 33,337 healthy European individuals from the Exome Aggregation Consortium. We compared distribution of genotype using the chi‐square test and logistic regression. In the exploratory cohort analyzed by WES, frequency of the TA allele of HSD17B13 rs72613567 was significantly decreased in HCC patients compared to healthy controls (P = 1.52 × 10−06). In the validation cohort, frequency of TA allele carriers was also decreased in patients with CLD and without HCC (39%) compared to healthy individuals (47%; P < 0.0001). The protective effect of the TA allele of HSD17B13 rs72613567 was identified in patients with ALD (odds ratio [OR] = 0.73; 95% confidence interval [CI], 0.65‐0.82; P < 0.0001), NAFLD (OR = 0.64; 95% CI, 0.49‐0.83; P = 0.0007), and hepatitis C (OR = 0.71; 95% CI, 0.60‐0.85; P = 0.0002). In patients with ALD, the proportion of TA allele carriers with HCC was significantly lower (32%) than in CLD patients without HCC (40%), even after adjustment for age, sex, and fibrosis (OR = 0.64; 95% CI, 0.46‐0.87; P = 0.005). Conclusion: The HSD17B13 rs72613567 loss of function variant is protective of HCC development in patients with ALD.

Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3‐rs738409, TM6SF2‐rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 [CI95%:1.16–2.40], p = 0.005; OR = 1.45 [CI95%:1.08–1.94], p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4‐rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 [CI95%:2.52–6.06], p = 1.14E‐09; OR = 1.79 [CI95%:1.25–2.56], p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 [CI95%:1.22–3.92], p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3‐rs738409 and TM6SF2‐rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.

Background: Proteoglycans are involved in neoangiogenesis and transduction of oncogenic signals, two hallmarks of carcinogenesis.Methods: This study sought to assess the prognostic value of serum levels of three proteoglycans (endocan, syndecan-1, and glypican-3) and VEGF in 295 patients with alcoholic cirrhosis: 170 without hepatocellular carcinoma, 58 with early hepatocellular carcinoma, and 67 with advanced hepatocellular carcinoma at inclusion. We analyzed the association between proteoglycan levels and prognosis using Kaplan-Meier and Cox methods.Results: Serum levels of the three proteoglycans and VEGF were increased in patients with advanced hepatocellular carcinoma compared with those without hepatocellular carcinoma or with early hepatocellular carcinoma. In multivariate analysis, high levels of serum endocan (>5 ng/mL) were independently associated with death [HR, 2.84; 95% confidence interval (CI,) 1.18-6.84; P ¼ 0.02], but not with hepatocellular carcinoma occurrence, in patients without hepatocellular carcinoma at baseline. High serum endocan (>5 ng/mL) and syndecan-1 (>50 ng/mL) levels were significantly associated with greater risk of tumor recurrence (P ¼ 0.025) in patients with early hepatocellular carcinoma treated by radiofrequency ablation. In patients with advanced hepatocellular carcinoma, high serum levels of endocan (P ¼ 0.004) and syndecan-1 (P ¼ 0.006) were significantly associated with less favorable overall survival. However, only a high level of serum syndecan-1 (>50 ng/mL) was independently associated with greater risk of death (HR, 6.21 95% CI,; P ¼ 0.0025).Conclusion: Serum endocan and syndecan-1 are easily assessable prognostic serum biomarkers of overall survival in alcoholic cirrhosis with and without hepatocellular carcinoma.Impact: These new biomarkers will be useful to manage patients with hepatocellular carcinoma developed on alcoholic cirrhosis. Cancer Epidemiol Biomarkers Prev; 22(8); 1343-52. Ó2013 AACR.

The aryl hydrocarbon receptor (AhR) is a transcription factor which is activated by diverse compounds and regulates the expression of xenobiotic metabolism genes. Recent studies have unraveled unsuspected physiological roles and novel alternative ligand-specific pathways for this receptor. In this review, we discuss these novel aspects and focus on the different responses elicited by the diverse endogenous and/or exogenous AhR ligands. In addition to challenging the relevance of the 'agonist/antagonist' classification of ligands, we introduce the concept of AhR plasticity as a primordial factor in the generation of these pathways. Finally, we suggest several promising perspectives for the pharmacological modulation of these responses.

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