Dataset Information

Nuclear BAP1 loss is common in intrahepatic cholangiocarcinoma and a subtype of hepatocellular carcinoma but rare in pancreatic ductal adenocarcinoma.

ABSTRACT: Deletion in the 3p21 region, the chromosomal location of BAP1, has been reported in a subset of hepatocellular carcinoma (HCC), biliary and pancreatic cancers. This suggests that BAP1 could play a role in the pathogenesis of these tumors. We assessed the frequency of BAP1 loss by immunohistochemistry in 103 hepatic, biliary and pancreatic cancers. We also assessed chromosomal alterations in the BAP1 region in the same tumors by genotyping. We identified high frequency 4/8 (50%) of BAP1 loss in intrahepatic cholangicarcinoma (ICC). However the frequency was lower in HCC 9/51 (17.6%), pancreatic 1/42(2.4%) and extrahepatic biliary cancers (0/2). Loss of heterozygosity of at least one marker from the 3p21 region was observed in 75% of ICC, 52.9% of HCC and 45.2% of pancreatic cancers. Expression of hepatocytic (HepPar1) and bile duct (cytokeratin 7) markers were common (7/9, 77.8%) in the HCC tumors with loss or decrease of BAP1 compared with those with preserved BAP1 (18/42, 42.9%), (Fisher exact p?=?0.0751). Our results confirm the high frequency of BAP1 alterations in ICC and low frequency in pancreatic cancers. It also suggests that BAP1 is commonly altered in a subtype of HCC with both hepatocytic and biliary differentiation. Further studies of the therapeutic implications of our findings are warranted.

SUBMITTER: Mosbeh A

PROVIDER: S-EPMC5996975 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Nuclear BAP1 loss is common in intrahepatic cholangiocarcinoma and a subtype of hepatocellular carcinoma but rare in pancreatic ductal adenocarcinoma.

Mosbeh Asmaa A Halfawy Khalil K Abdel-Mageed Wael S WS Sweed Dina D Rahman Mohamed H Abdel MHA

Cancer genetics 20180409

Deletion in the 3p21 region, the chromosomal location of BAP1, has been reported in a subset of hepatocellular carcinoma (HCC), biliary and pancreatic cancers. This suggests that BAP1 could play a role in the pathogenesis of these tumors. We assessed the frequency of BAP1 loss by immunohistochemistry in 103 hepatic, biliary and pancreatic cancers. We also assessed chromosomal alterations in the BAP1 region in the same tumors by genotyping. We identified high frequency 4/8 (50%) of BAP1 loss in i ...[more]

PMID: 29778232

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Project description:ObjectivesTo establish a nomogram based on preoperative laboratory study variables using least absolute shrinkage and selection operator (LASSO) regression for differentiating combined hepatocellular cholangiocarcinoma (cHCC) from intrahepatic cholangiocarcinoma (iCCA).MethodsWe performed a retrospective analysis of iCCA and cHCC patients who underwent liver resection. Blood signatures were established using LASSO regression, and then, the clinical risk factors based on the multivariate logistic regression and blood signatures were combined to establish a nomogram for a differential preoperative diagnosis between iCCA and cHCC. The differential accuracy ability of the nomogram was determined by Harrell's index (C-index) and decision curve analysis, and the results were validated using a validation set. Furthermore, patients were categorized into two groups according to the optimal cut-off values of the nomogram-based scores, and their survival differences were assessed using Kaplan-Meier curves.ResultsA total of 587 patients who underwent curative liver resection for iCCA or cHCC between January 2008 and December 2017 at West China Hospital were enrolled in this study. The cHCC score was based on the personalized levels of the seven laboratory study variables. On multivariate logistic analysis, the independent factors for distinguishing cHCC were age, sex, biliary duct stones, and portal hypertension, all of which were incorporated into the nomogram combined with the cHCC-score. The nomogram had a good discriminating capability, with a C-index of 0.796 (95% CI, 0.752-0.840). The calibration plot for distinguishing cHCC from iCCA showed optimal agreement between the nomogram prediction and actual observation in the training and validation sets. The decision curves indicated significant clinical usefulness.ConclusionThe nomogram showed good accuracy for the differential diagnosis between iCCA and cHCC preoperatively, and therapeutic decisions would improve if it was applied in clinical practice.

Project description:IntroductionIntrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.Case presentationWe present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.ConclusionThese findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.

Dataset Information

Nuclear BAP1 loss is common in intrahepatic cholangiocarcinoma and a subtype of hepatocellular carcinoma but rare in pancreatic ductal adenocarcinoma.

Publications

Nuclear BAP1 loss is common in intrahepatic cholangiocarcinoma and a subtype of hepatocellular carcinoma but rare in pancreatic ductal adenocarcinoma.

Similar Datasets

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