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BAP1 is a haploinsufficient tumor suppressor linking chronic pancreatitis to pancreatic cancer in mice

Author

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  • Stephanie Perkail

    (GWU School of Medicine and Health Sciences
    GWU School of Medicine and Health Sciences)

  • Jaclyn Andricovich

    (GWU School of Medicine and Health Sciences
    GWU School of Medicine and Health Sciences)

  • Yan Kai

    (GWU School of Medicine and Health Sciences
    GWU School of Medicine and Health Sciences
    Dana-Farber Cancer Institute)

  • Alexandros Tzatsos

    (GWU School of Medicine and Health Sciences
    GWU School of Medicine and Health Sciences)

Abstract

Chronic pancreatitis represents a risk factor for the development of pancreatic cancer. We find that heterozygous loss of histone H2A lysine 119 deubiquitinase BAP1 (BRCA1 Associated Protein-1) associates with a history of chronic pancreatitis and occurs in 25% of pancreatic ductal adenocarcinomas and 40% of acinar cell carcinomas. Deletion or heterozygous loss of Bap1 in murine pancreata causes genomic instability, tissue damage, and pancreatitis with full penetrance. Concomitant expression of KrasG12D leads to predominantly intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, while pancreatic intraepithelial neoplasias are rarely detected. These lesions progress to metastatic pancreatic cancer with high frequency. Lesions with histological features mimicking Acinar Cell Carcinomas are also observed in some tumors. Heterozygous mice also develop pancreatic cancer suggesting a haploinsufficient tumor suppressor role for BAP1. Mechanistically, BAP1 regulates genomic stability, in a catalytic independent manner, and its loss confers sensitivity to irradiation and platinum-based chemotherapy in pancreatic cancer.

Suggested Citation

  • Stephanie Perkail & Jaclyn Andricovich & Yan Kai & Alexandros Tzatsos, 2020. "BAP1 is a haploinsufficient tumor suppressor linking chronic pancreatitis to pancreatic cancer in mice," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16589-8
    DOI: 10.1038/s41467-020-16589-8
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    Cited by:

    1. Laura Rüland & Francesco Andreatta & Simone Massalini & Susana Chuva de Sousa Lopes & Hans Clevers & Delilah Hendriks & Benedetta Artegiani, 2023. "Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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