- Email: [email protected]
993 INFLUENCE OF CHEMOKINE RANTES PROMOTER DIMORPHISMS ON HEPATOCELLULAR CARCINOMA OCCURRENCE IN PATIENTS WITH CIRRHOSIS
POSTERS detection of new biomarkers for Hepatocellular carcinoma (HCC) is highly needed. We focused on Natural antisense transcripts (NATs), which constitute a class of non-coding RNAs that emerged as important regulators of gene expression. We analyzed NATs expression of HCC to find a novel molecular marker using custom microarray. Methods: 29 patients with HCC were investigated; Hepatitis B virus (HBV) and Hepatitis C virus (HCV)-free HCC (8 cases), HBVassociated HCC (4 cases), HCV-associated HCC (16 cases), and HBV and HCV-associated HCC (1 case). Total RNAs isolated from HCC tissues and corresponding non-cancerous liver tissues from surgically resected samples were subjected to expression analysis using a custom-microarray containing human sense/antisense probes for ca. 21,000 genes. Examination items of sense/antisense RNA were as follows i. HCC and non-cancerous liver tissue, and ii. viral infection of non-cancerous liver tissue. Results: i. 864 RNA including 285 NATs were identified as up- and downregulated in HCC tissues, compared to non-cancerous liver tissue (P < 0.001, fold change > 2.0). Hierarchical clustering of antisense RNA clearly distinguished HCC and normal liver tissue with or without viral infection. ii. We analyzed the influence of viral infection at non-cancerous liver tissue, 316 RNA including 169 NATs were identified as up- and down-regulated between historical background of viral infection (P < 0.001). Cluster analysis revealed that NATs expression was significantly correlated with the viral infection of HBV or HCV. Conclusions: Our study suggests that NATs expression of HCC is significantly different from normal liver tissue. Expression profiling of NATs is effective techniques for diagnosis of HCC carcinogenesis. In addition, analysis of the obtained NATs is helpful to understand the molecular changes in HCC progression and may lead to the identification of new targets for HCC diagnosis. 992 GENETIC VARIANTS IN MYELOPEROXIDASE AND CATALASE PROMOTERS CONFER SUSCEPTIBILITY TO HEPATOCELLULAR CARCINOMA OCCURRENCE IN PATIENTS WITH HCV-RELATED CIRRHOSIS P. Nahon1 , A. Sutton2 , P. Rufat3 , N. Charnaux2 , A. Mansouri4 , N. Ganne-Carrie´ 1 , J.-C. Trinchet1 , D. Pessayre4 , M. Beaugrand1 . 1 Hˆ opital Jean Verdier, AP-HP, Bondy, 2 Universit´e Paris 13-UFR SMBH / INSERM U698, Bobigny, 3 Groupe Hospitalier Piti´e-Salpˆetri`ere, AP-HP, 4 INSERM, U773, Centre de Recherche Bichat Beaujon CRB3, Universit´e Paris 7, Paris, France E-mail: [email protected] Background and Aims: Genetic variants affecting the activity of pro- or antioxidant enzymes could influence carcinogenesis in HCV-infected patients. In mitochondria, the manganese superoxide dismutase (MnSOD) converts superoxide anion into hydrogen peroxide (H2 O2 ), which, if not detoxified by glutathione peroxidase 1 (GPx1) can be then transformed by myeloperoxidase (MPO) into highly reactive hypochlorite anion (ClO− ), or spread outside mitochondria where it will be detoxified by peroxysomal catalase (CAT) into water. The Ala16Val-MnSOD, Pro198LeuGPx1, G463A-MPO and T262C-CAT dimorphisms confer increased enzymatic activity respectively for Ala-MnSOD, Pro198-GPx1, G463MPO and T262-CAT variants. Patients and Methods: In a cohort of 204 patients with HCV-related cirrhosis prospectively followed-up for hepatocellular carcinoma (HCC) screening, genotypes associated with these four enzymes were determined. Their influence on HCC occurrence, alone or combined, was prospectively assessed using Kaplan–Meier Method.
Results: During follow-up (103.2±3.4 months), 84/204 patients (41.1%) developed HCC, and 78/204 (38.2%) died. The 2G-MPO genotype was a risk factor for HCC occurrence (HR = 2.8 [1.7–4.4]; first quartile time to HCC occurrence: 45 vs. 96 months; LogRank<0.0001) as well as the 2C-CAT genotype (HR = 1.74 [1.06– 2.82]; first quartile time to HCC occurrence: 55 vs. 96 months; LogRank = 0.02) while the Ala16Val-MnSOD and Pro198Leu-GPx1 dimorphisms had no influence on this event. Four groups of patients were constituted according to the association of their MPO and catalase genotypes reflecting a progessive increase in ClO- and cytosolic H2 O2 productions [Group 1: 1or2A-MPO/1or2T-CAT (20%), Group 2: 1or2A-MPO/2C-CAT (30%), Group 3: 2G-MPO/1or2T-CAT (13%), Group 4: 2G-MPO/2C-CAT (37%)]. The risk of HCC occurrence increased gradually from Group 1 to 4 with corresponding hazard ratios from Group 2 to 4: HR = 2.05 [0.9–4.6] (P = 0.08), HR = 3.8 [1.5–9.1] (P = 0.002), and HR = 4.8 [2.2–10.4] (P < 0.0001) respectively when considering Group 1 as reference. Corresponding 5 years incidences were 2.5% (Group 1), 17.9% Groups 2 and 3) and 38.9% (Group 4). Conclusions: Genetic heterogeneity of pro- or antioxidant systems modulating cytosolic H2 O2 and ClO− accumulation influences the risk of HCC occurrence in patients with HCV-related cirrhosis. 993 INFLUENCE OF CHEMOKINE RANTES PROMOTER DIMORPHISMS ON HEPATOCELLULAR CARCINOMA OCCURRENCE IN PATIENTS WITH CIRRHOSIS F. Charni1 , A. Sutton1 , P. Rufat2 , J.-C. Trinchet3 , M. Beaugrand3 , N. Charnaux1 , P. Nahon3,4 . 1 INSERM U698, UFR SMBH, Universit´e Paris 13, Bobigny, 2 Groupe Hospitalier Piti´e-Salpˆetri`ere, AP-HP, Paris, 3 Hˆ opital Jean Verdier, AP-HP, Bondy, 4 INSERM, U773, Centre de Recherche Bichat Beaujon CRB3, Universit´e Paris 7, Paris, France E-mail: [email protected] Background and Aims: Chemokine RANTES (Regulated upon activation normal T cells expressed and secreted) is implicated in the initial steps of liver inflammation and the promotion of various human cancers. The aim of this study was to explore the influence of two functional genetic polymorphisms in RANTES promoter on the risk of hepatocellular carcinoma (HCC) occurrence in patients with cirrhosis. Methods: RANTES −28C/G and −403G/A promoter dimorphisms and RANTES serum levels were assessed in 243 HCV-infected patients and 253 alcoholic patients, included at time of cirrhosis diagnosis and prospectively followed-up for HCC screening, chemokine RANTES expression being increased by the −28C or −403A variant. Results: During a mean time of follow-up of 76 months, 137 (27.6%) patients developed HCC and 162 (32.6%) died or were transplanted. The two studied SNP did not influence disease severity or RANTES sera levels at inclusion. During follow-up, patients with alcoholic cirrhosis bearing two copies of the RANTES −403G variant had a higher rate of HCC occurrence when compared to patients carrying at least one RANTES −403A allele (26.3% vs 8.2%, P = 0.0004). Using the Kaplan–Meier method, the −403GG RANTES genotype was a risk factor for HCC occurrence (HR = 3.0 [1.3–5.8]; first quartile time to HCC occurrence: 60 vs. 120 months; LogRank = 0.007) and death (HR = 1.4 [1.0–2.0]; first quartile time to death: 36 vs. 36 months; LogRank = 0.01) in this sub-group. In contrast, carriage of the RANTES −403GG genotype was not associated with HCC development or death in patients with HCV-related cirrhosis. The −28C/G dimorphim did not influence the occurrence of death or HCC during follow-up in this cohort, whatever the cause of cirrhosis. Conclusions: This study suggests an influence of the chemokine RANTES −403G/A promoter dimorphism on hepatocellular carcinoma occurrence in patients with cirrhosis, that may further depend upon the etiology underlying liver disease.
Journal of Hepatology 2011 vol. 54 | S363–S534
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Results: During follow-up (103.2±3.4 months), 84/204 patients (41.1%) developed HCC, and 78/204 (38.2%) died. The 2G-MPO genotype was a risk factor for HCC occurrence (HR = 2.8 [1.7–4.4]; first quartile time to HCC occurrence: 45 vs. 96 months; LogRank<0.0001) as well as the 2C-CAT genotype (HR = 1.74 [1.06– 2.82]; first quartile time to HCC occurrence: 55 vs. 96 months; LogRank = 0.02) while the Ala16Val-MnSOD and Pro198Leu-GPx1 dimorphisms had no influence on this event. Four groups of patients were constituted according to the association of their MPO and catalase genotypes reflecting a progessive increase in ClO- and cytosolic H2 O2 productions [Group 1: 1or2A-MPO/1or2T-CAT (20%), Group 2: 1or2A-MPO/2C-CAT (30%), Group 3: 2G-MPO/1or2T-CAT (13%), Group 4: 2G-MPO/2C-CAT (37%)]. The risk of HCC occurrence increased gradually from Group 1 to 4 with corresponding hazard ratios from Group 2 to 4: HR = 2.05 [0.9–4.6] (P = 0.08), HR = 3.8 [1.5–9.1] (P = 0.002), and HR = 4.8 [2.2–10.4] (P < 0.0001) respectively when considering Group 1 as reference. Corresponding 5 years incidences were 2.5% (Group 1), 17.9% Groups 2 and 3) and 38.9% (Group 4). Conclusions: Genetic heterogeneity of pro- or antioxidant systems modulating cytosolic H2 O2 and ClO− accumulation influences the risk of HCC occurrence in patients with HCV-related cirrhosis. 993 INFLUENCE OF CHEMOKINE RANTES PROMOTER DIMORPHISMS ON HEPATOCELLULAR CARCINOMA OCCURRENCE IN PATIENTS WITH CIRRHOSIS F. Charni1 , A. Sutton1 , P. Rufat2 , J.-C. Trinchet3 , M. Beaugrand3 , N. Charnaux1 , P. Nahon3,4 . 1 INSERM U698, UFR SMBH, Universit´e Paris 13, Bobigny, 2 Groupe Hospitalier Piti´e-Salpˆetri`ere, AP-HP, Paris, 3 Hˆ opital Jean Verdier, AP-HP, Bondy, 4 INSERM, U773, Centre de Recherche Bichat Beaujon CRB3, Universit´e Paris 7, Paris, France E-mail: [email protected] Background and Aims: Chemokine RANTES (Regulated upon activation normal T cells expressed and secreted) is implicated in the initial steps of liver inflammation and the promotion of various human cancers. The aim of this study was to explore the influence of two functional genetic polymorphisms in RANTES promoter on the risk of hepatocellular carcinoma (HCC) occurrence in patients with cirrhosis. Methods: RANTES −28C/G and −403G/A promoter dimorphisms and RANTES serum levels were assessed in 243 HCV-infected patients and 253 alcoholic patients, included at time of cirrhosis diagnosis and prospectively followed-up for HCC screening, chemokine RANTES expression being increased by the −28C or −403A variant. Results: During a mean time of follow-up of 76 months, 137 (27.6%) patients developed HCC and 162 (32.6%) died or were transplanted. The two studied SNP did not influence disease severity or RANTES sera levels at inclusion. During follow-up, patients with alcoholic cirrhosis bearing two copies of the RANTES −403G variant had a higher rate of HCC occurrence when compared to patients carrying at least one RANTES −403A allele (26.3% vs 8.2%, P = 0.0004). Using the Kaplan–Meier method, the −403GG RANTES genotype was a risk factor for HCC occurrence (HR = 3.0 [1.3–5.8]; first quartile time to HCC occurrence: 60 vs. 120 months; LogRank = 0.007) and death (HR = 1.4 [1.0–2.0]; first quartile time to death: 36 vs. 36 months; LogRank = 0.01) in this sub-group. In contrast, carriage of the RANTES −403GG genotype was not associated with HCC development or death in patients with HCV-related cirrhosis. The −28C/G dimorphim did not influence the occurrence of death or HCC during follow-up in this cohort, whatever the cause of cirrhosis. Conclusions: This study suggests an influence of the chemokine RANTES −403G/A promoter dimorphism on hepatocellular carcinoma occurrence in patients with cirrhosis, that may further depend upon the etiology underlying liver disease.
Journal of Hepatology 2011 vol. 54 | S363–S534
S395