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1150A AASLD ABSTRACTS HEPATOLOGY, October, 2015 and diagnoses of patients who were initially thought to have DILI, which was later judged to be unlikely. Methods: Between 2004 and 2014, the Drug Induced Liver Injury Network (DILIN) Prospective Study recruited and assessed 1405 patients suspected to have DILI. All patients underwent evaluation for viral hepatitis (A, B, C, CMV, E, HSV), autoimmune hepatitis, pancreaticobiliary disease, and alcohol. Cases under went a structured causality assessment at 6 months of follow-up to be assigned into 5 categories of likelihood (definite, >95%; highly likely, 75-94%; probable, 50-74%, possible, 25-49%, unlikely,
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 1151A 1933 Genome-wide investigation identifies common SNPs on Chr9p22.2 as risk factors for liver injury due to sulfamethoxazole/trimethoprim Thomas J. Urban 1,2 , Paola Nicoletti 3 , Robert J. Fontana 4 , Andrew Stolz 5 , Ann K. Daly 6 , Guruprasad P. Aithal 7 , M. I. Lucena 8 , Huiman X. Barnhart 9 , Paul Watkins 2 , Naga P. Chalasani 10 ; 1 Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC; 2 Hamner Institute for Drug Safety Sciences, Durham, NC; 3 Columbia University, New York, NY; 4 University of Michigan, Ann Arbor, MI; 5 University of Southern California, Los Angeles, CA; 6 University of Newcastle, Newcastle upon Tyne, United Kingdom; 7 Nottingham University, Nottingham, United Kingdom; 8 University of Malaga, Malaga, Spain; 9 Duke University, Durham, NC; 10 Indiana University School of Medicine, Indianapolis, IN BACKGROUND &AIM: Treatment with the antibiotic combination sulfamethoxazole/trimethoprim (SMZ/TMP) can result in a rare but serious liver toxicity which typically presents with immunoallergic features. Currently there are no genetic or non-genetic predictors of toxicity. We aimed to uncover genetic risk factors associated with SMZ/TMP DILI. METHODS: Genomewide genotyping was performed on 27 individuals of European ancestry who experienced liver injury from SMZ/TMP, including 22 DILIN patients and 5 from iDILIC/iSAEC. Genotype frequencies were compared to >5,000 population controls. Targeted genotyping by TaqMan assay was performed for validation in 33 cases (19 cases included in the GWAS and 14 new cases not included in the GWAS). RESULTS: GWAS was conducted on 27 individuals with SMZ/TMP DILI with mean age 47 years, 48% females, and the pattern of liver injury was hepatocellular in 41% and cholestatic in 30%. Their peak ALT (mean ± sd) were 714 ± 542 U/L and peak bilirubin 11.5± 10.1 mg/dL. The GWAS revealed a set of common SNPs in an intergenic region on Chr9p22.2 that showed strong evidence of association with SMZ/TMP-DILI. The minor allele frequency (MAF) of the risk allele was 26% in SMZ/TMP-DILI cases, vs. 4.6% in controls (OR: 9.0, 95%CI: 4.3-19.1, p = 5 X 10 -9 ). Validation cohort consisted of 33 European Caucasians (19 from the GWAS plus 14 independent replication samples) with mean age 46 years, 55% females and the pattern of liver injury was hepatocellular in 28% and cholestatic in 32%. Their peak ALT values were 745 ± 695 U/L and bilirubin 13.1± 10.1 mg/ dL. Targeted assays confirmed the genotypes as measured by the GWAS arrays, and further identified 4 additional carriers among 14 new cases in the validation cohort (MAF=14.3%, p < 0.05). However, the phenotypic characteristics of DILI in patients who carried the risk alleles (age, sex, latency to onset, immunoallergic features, peak laboratory test values) were not significantly different from those who lacked the risk alleles at Chr9p22.2. CONCLUSIONS: Common SNPs on Chr9p22.2 are strongly associated with risk for SMX/TMP-DILI. These SNPs are not located near any known protein-coding gene or miRNA, and have not previously been associated with mRNA expression of any gene. Further <strong>studies</strong> will be necessary to understand the mechanism underlying the association, and to extend these <strong>studies</strong> to other hypersensitivity reactions to SMZ/ TMP as well as to DILI caused by other sulfonamides. Disclosures: Robert J. Fontana - Consulting: GlaxoSmithKline, CLDF; Grant/Research Support: Gilead, vertex, BMS, Jansen, Gilead Naga P. Chalasani - Consulting: Abbvie, Lilly, Celgene, Tobira, NuSirt, Takeda, Merck/Anthem, Salix; Grant/Research Support: Intercept, Gilead, Galectin The following authors have nothing to disclose: Thomas J. Urban, Paola Nicoletti, Andrew Stolz, Ann K. Daly, Guruprasad P. Aithal, M. I. Lucena, Huiman X. Barnhart, Paul Watkins 1934 Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via mTORC1/FASN pathway in mice Junjie Hu 2,1 , Lei Li 3,1 , Li Che 1 , Diego Calvisi 4 , Xin Chen 1 ; 1 Bioengineering and Therapeutic Sciences, UCSF, San Francisoco, CA; 2 School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China; 3 School of Pharmacy, Huazhong university of science and technology, Wuhan, China; 4 Institude of Pathology, university of greifswald, Greifswald, Germany Background: Activation of the AKT/mTOR cascade and overexpression of c-Met have been implicated in the development of human hepatocellular carcinoma (HCC). Methods: To elucidate the functional crosstalk between the AKT and c-Met pathways, we generated a model characterized by the combined expression of activated AKT and c-Met in the mouse liver using hydrodynamic transfection. Results: We found that co-expression of AKT and c-Met results in faster liver tumor development when compared with mice overexpressing AKT alone, whereas c-Met alone does not lead to tumor formation. At the molecular level, liver tumors induced by AKT/c-Met display activation of AKT/mTOR and Ras/MAPK cascades as well as increased lipogenesis and glycolysis. Mechanistically, AKT/c-Met driven hepatocarcinogenesis was found to be mTORC1-dependent, as Raptor genetic deletion abrogates tumor development in AKT/ c-Met mice. Furthermore, since increased de novo synthesis of fatty acid is a pivotal metabolic event downstream of mTORC1, we determined the requirement of lipogenesis in AKT/c-Met driven liver tumor development using conditional Fatty Acid Synthase (FASN) knockout mice. Of note, hepatocarcinogenesis induced by AKT/c-Met was fully inhibited by FASN ablation. In human HCC samples, coordinated expression of FASN, c-Met, activated AKT and ERK proteins was detected in a subgroup of biologically aggressive tumors. Conclutions: Our study demonstrates that co-activation of AKT and c-Met induces HCC development that depends on the mTORC1/FASN pathway. Suppression of mTORC1 and/or FASN might be highly detrimental for the growth of human HCC subsets characterized by concomitant induction of the AKT and c-Met cascades. Disclosures: The following authors have nothing to disclose: Junjie Hu, Lei Li, Li Che, Diego Calvisi, Xin Chen 1935 Classification of tumors based on the integrated profile of genetic and epigenetic alterations and the biological behavior of human hepatocellular carcinoma Naoshi Nishida 1 , Toshimi Kaido 2 , Masatoshi Kudo 1 ; 1 Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-sayama, Japan; 2 Department of Surgery, Graduate School of Medicine Kyoto University, Kyoto, Japan Aims: We tried to classify HCCs based on the integrated genetic and epigenetic profile, and examined the association between the classification and biological characteristics such as high metastatic potential. Methods: (1) A total of 121 HCCs were examined for p53, β-catenin and TERT promoter mutation, methylation of 8 tumor suppressor genes (TSGs) and hypomethylation on 3 repetitive DNA sequences (RSs), and fractional allelic loss (FAL) as a surrogate marker of chromosomal instability (CI) using direct sequencing, MethyLight, and microsatellite analyses with 200 markers, respectively. A degree of TSG methylation and hypomethylation of RSs was categorized as “extensive” vs. “limited” and “significant” vs. “slight” by hierarchical clustering, respectively. Each tumor was
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208A AASLD ABSTRACTS HEPATOLOGY, Oc
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1000A AASLD ABSTRACTS HEPATOLOGY, O
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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