ABSTRACT FINAL ID: 1796
TITLE: Jagged1 is associated with poor prognosis of HBV-related liver cancer
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Introduction: HBV and HCV infections are the major etiological factors in liver cancer but the mechanisms of liver carcinogenesis and clinical features are different. We previously reported that genomic alterations in liver cancer are associated with a specific expression profile in AFP-producing hepatoma cells and involve the Notch ligand gene, Jagged1, as demonstrated by in vitro and in vivo analysis. Moreover, we found Jagged1 genomic amplification was associated with a poor prognosis. Using clinical samples, we assessed the presence of the Notch signaling abnormality, including whether a specific etiologic factor was associated with this abnormality.
Methods: We evaluated 115 liver cancer FFPE tissues (median age 64±9.7 years; 89 men, 26 women) that had been surgically resected in the period from 2004 to 2010 in our hospital and evaluated their clinical characteristics. There were 31 cases of HBV-related liver cancer, 54 cases of HCV-related cancer, 1 case of HBV and HCV mixed cancer, and 29 cases of non-HBV and non-HCV (NBNC) cancer. RNA was isolated from 38 frozen liver cancer tissues (HBV, 17 cases; HCV, 18 cases; NBNC, 3 cases) and the expression of Notch-related genes was analyzed by RTD-PCR. Jagged1 expression and copy number variation in the genomic DNA were determined and the outcome of therapy including survival was compared.
Results: After classifying the liver cancer cases by the etiologies of HBV, HCV and NBNC, Jagged1 copy number elevation was found in 21 of 37 HBV cases (57%), 33 of 55 HCV cases (66%), and 15 of 29 NBNC cases (52%). High AFP was seen in 13 of 32 HBV cases (40%), 16 of 56 HCV cases (29%), and 10 of 29 NBNC cases (34%). We found a significant association between Jagged1, Notch1, and HES1 expression (p<0.01); moreover, Jagged1 genomic copy number variation was correlated with Jagged1 expression in AFP-upregulated cases (p<0.05). We could not observe any difference in overall survival between the three groups. However, analysis of prognosis of HBV-related cancer showed that Jagged1-amplified cases (CNV ≥1.5) showed a poor prognosis compared with non-amplified cases(p<0.05). On the other hand, HCV- and NBNC-related liver cancer did not influence prognosis in Jagged1-amplified cases. In HBV cases, higher CNV was associated with vascular invasion noted at the surgical operation (p<0.05). On the other hand, Jagged1 enhancement in HCV-related liver cancer was not associated with vascular invasion.
Conclusion: HBV-related liver cancer demonstrated Jagged1 genome amplification, which corresponded to shorter survival times, and this was associated with vascular invasion.