582 EXPRESSION OF HDAC ISOENZYMES AS A PROGNOSTIC MARKER IN HEPATOCELLULAR CARCINOMA

POSTERS were analyzed for the presence of mutation on 8 genes (TP53, CTNNB1, AXIN1, H-/K-/N-RAS, BRAF, PTEN). In addition, tumors were genotyped with diallelic markers for 14 chromosome arms frequently deleted in PLC. Results: One third of HCCs were presenting Wnt pathway alterations either on CTNNB1 (25%) or AXIN1 (7%). One hepatocellular and one cholangiocellular tumors were mutated for the RAS pathway. Among the rare TP53 mutations (7%), one was a R249S transversion, hallmark of aflatoxin B1 (AFB1) exposure. This mutation occured in the tumor from a HBs(+) patient who lifelong resided in Romania. Chromosome instability (CIN), was not restricted as elsewhere in Europe to chromosomes 17p and 8p but was rather involving several additional targets. The mean Fractional Allelic Loss (FAL) was 30% in HCC and 37% in cholangiocellular carcinomas i.e. values similar to that observed in regions with high mutagen exposure like Eastern-Asia. HCC patients living in cities were significantly younger than those from the countryside (mean 59±9 vs 66±6 y.o., P = 0.03) and presented less differentiated tumors (Edmonson-Steiner III-IV 83 vs 30%, P = 0.01) with a trend for a higher CIN (FAL 33±8 vs 23±10 %, P = 0.08, NS). Conclusions: Molecular epidemiology of PLC in Romania is distinct from that observed in western Europe with a conspicuous high CIN. Furthermore, our data indicate that in selected cases AFB1 may play a role in liver tumorigenesis. The major differences observed between rural and urban patients emphasize the potentially important role played by environmental exposures in Romania. An increase of patients recruitment in the current series is, however, mandatory to confirm this preliminary analysis. 581 A VARIANT IN MICRORNA-196A2 IS ASSOCIATED WITH SUSCEPTIBILITY TO HEPATOCELLULAR CARCINOMA IN MALE CHINESE PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION P. Qi1 , T.-H. Dou2 , F.-G. Zhou3 , X. Gu1 , H. Wang4 , C.-F. Gao1 . 1 Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, 2 Department of Microbiology, School of Life Sciences, Fudan University, 3 Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, 4 Department of Laboratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China E-mail: [email protected] Background and Aims: MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions as tumor suppressors and oncogenes. Recent studies have implicated that the rs11614913 SNP in miR-196a2 was associated with susceptibility of lung cancer, congenital heart disease, breast cancer and shortened survival time of non-small cell lung cancer. In light of the important role of miRNAs in hepatocellular carcinoma (HCC) development and progression, we hypothesized that this functional SNP was also associated with the susceptibility and/or progression of hepatitis B virus (HBV)-related HCC. Methods: A total of 560 patients with chronic HBV infection and 391 healthy volunteers were enrolled, and miR-196a2 polymorphism was genotyped by polymerase chain reactionligation detection reaction (PCR-LDR). Results: In our study group, there was no significant association between miR-196a2 polymorphism and the risk of HBV-related HCC in all subjects, however, the risk of HCC was significantly higher with miR-196a2 CC genotype or C allele compared with those with the TT genotype or T allele in male patients. Furthermore, in a subsequent analysis of the association between this polymorphism and clinicopathological characteristics, there was still no significant difference in both the distribution of genotype or allelic frequency. Interestingly, we observed that the T allele was significantly more frequent in male HCC patients with lymphatic metastasis. S230

Conclusions: Our results suggested that miR-196a2 polymorphism was associated with susceptibility to HBV-related HCC in a male Chinese population. 582 EXPRESSION OF HDAC ISOENZYMES AS A PROGNOSTIC MARKER IN HEPATOCELLULAR CARCINOMA K. Quint1 , A. Agaimy2 , C. Steindorf3 , C. Hellerbrand4 , M. Ocker1 . 1 Institute for Surgical Research, Philipps University Marburg, Marburg, 2 Institute of Pathology, 3 Medicine 1, University Hospital Erlangen, Erlangen, 4 Medicine 1, University Hospital Regensburg, Regensburg, Germany E-mail: [email protected] Background: Histone deacetylases (HDAC) are enzymes that are responsible for the transcriptional control of genes through modifications of histone proteins. Among others, they play a factor in the control of tumor suppressor genes. Hypoacetylated histone proteins have been associated with precancerous and malignant lesions and from other tumor entities we know that HDAC expression is an independent prognostic factor. Since inhibitors of histone deacetylases (HDACi) emerge as promising therapeutics in the management of solid tumors, including hepatocellular carcinoma, we analyze the importance of HDAC expression as a prognostic marker in hepatocellular carcinoma. Methods: Tissue micro arrays of primary HCCs and adjacent normal tissue of 170 patients (male n = 145, 85.3%; female n = 25, 14.7%; mean age 61.9±11.0 years) were evaluated immunohistochemically for the expression of HDAC isoenzymes 1, 2 and 3 and ki-67 antigen. Intensity and extensity of expression were evaluated by two independent blinded observers and the data was correlated with histopathological and clinical criteria. Results: The staging of the analyzed specimens was pT1 35.6%, pT2 30.9%, pT3 31.5%, pT4 1.9% and the grading was G1 35.9%, G2 51.2%, G3 12.9%. The sum score of intensity and extensity of the HDAC isoenzymes correlated significantly (p < 0.001) with tumor grading (HDAC1 r = 0.453; HDAC2 r = 0.380; HDAC3 r = 0.441) and ki67 expression (HDAC1 r = 0.508; HDAC2 r = 0.333; HDAC3 r = 0.400). Intensity correlated stronger with grading than extensity. There was no correlation of HDAC expression with tumor staging. Conclusion: The expression of all three HDAC isoenzymes increases with grading and could be used as a new marker for the therapy of HCC with HDAC inhibitors. 583 TUMOR RESPONSE IN A PHASE 2 STUDY OF FIRST-LINE BRIVANIB IN HEPATOCELLULAR CARCINOMA (HCC): COMPARISON OF MODIFIED WHO AND MODIFIED RECIST CRITERIA J.-L. Raoul1 , R. Lencioni2 , J.-W. Park3 , C. Baudelet4 , I. Walters5 . 1 Department of Medical Oncology, Rennes, France; 2 University of Pisa, Pisa, Italy; 3 National Cancer Center, Goyang, Republic of Korea; 4 Bristol-Myers Squibb, Braine-l’Alleud, Belgium; 5 Bristol-Myers Squibb, Wallingford, CT, USA E-mail: [email protected] Background: Recent guidelines for HCC recommend alternative assessment of tumor responses using modified RECIST (mRECIST) taking into account the viability of tumors (JNCI, 2008). We report an independent review of imaging from the first-line cohort of a phase 2 brivanib study and compare results of tumor assessments obtained by modified WHO (mWHO) criteria and by mRECIST criteria. Methods: The dataset included a review of 55 patients with unresectable, locally advanced/metastatic, radiologically evaluable HCC who received no prior systemic therapy and were treated with brivanib 800 mg/d. An independent review committee had prospectively assessed tumor responses and time-to-progression (TTP) using mWHO criteria (ASCO 2009). Blinded scans were

Journal of Hepatology 2010 vol. 52 | S183–S317