Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of and loss-of-function mutations of () have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing -Cre mice bearing conditional alleles of mutant and/or floxed Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant alone (KA), bi-allelic loss of hepatic (BA), and heterozygous loss of in conjunction with mutant expression (BKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of in conjunction with mutant expression (BKA) developed discrete foci of HCC and ICC. Further, the median survival of BKA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in BKA mice and approximately 50 weeks in BA and KA mice ( < 0.001). Microarray analysis performed on liver tissue from KA and BKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.