부산대학교 도서관

Aims: BAP1 is a tumor suppressor gene that is mutated in several tumor types. BAP1 loss has been noted in 20% of intrahepatic cholangiocarcinomas and has been used in support of a diagnosis of cholangiocarcinoma (CCA) in intrahepatic masses. We sought to determine if BAP1 loss occurs in hepatocellular carcinoma (HCC) and to characterize the features of cases that show BAP1 loss. Methods: We screened 133 HCCs (1994-2012) for loss of BAP1 by immunohistochemistry (clone C-4) using tissue microarrays and followed up all abnormal (non-nuclear expression) cases and a group of control normal cases (n=24) by performing BAP1 IHC on full tissue sections. Loss of BAP1 IHC nuclear expression in the entire tumor was recorded as negative while loss in >5% but less than the entire tumor section was scored as heterogeneous loss. BAP1 chromogenic in situ hybridization (CISH) was performed on cases of BAP1 loss and scored as follows: negative (no staining), equivocal (rare cytoplasmic dots only at x40) and positive (cytoplasmic dots readily seen). Results: 35 (26%) HCC were abnormal on the initial screen. BAP1 IHC on full sections showed 7 (5.3%) HCC were negative, 8 (6.0%) showed heterogeneous for BAP1 loss and 20 were intact. CISH was successful in 6 and 8 cases with complete and heterogeneous BAP1 loss by IHC respectively. CISH was negative in 4 of 6 IHC negative cases and equivocal in 2 of 6, and was negative in 2 of 8 IHC heterogeneous cases, equivocal in 2 and positive in 4. CISH was positive in 14 (61%) of cases with controls, equivocal in 9 (38%) and negative in 1 (1%). HCC with BAP1 loss and heterogeneous loss are compared in the Table below. HCC with BAP1 loss were conventional type while HCC with heterogeneous BAP1 loss were conventional in 4 (50%) cases and steatohepatitic in 4 (50%) cases. Conclusions: BAP1 loss is seen in 5-10% of HCC limiting its usefulness in the diagnosis of intrahepatic CCA particularly on biopsy specimens. The complete loss of BAP1 in a subset of cases raises consideration for targeting BAP1-related pathways in the treating HCC.