Tumor Suppressor BRCA1 Associated Protein-1 (BAP1) in Pancreatic Cancer Open Access
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Chronic pancreatitis represents a well-known risk factor for the development of pancreatic cancer. Although the causative environmental and genetic factors are poorly understood, the accompanying inflammation results in tissue injury and accumulation of DNA damage which facilitates cellular transformation by oncogenic KRAS. We found that loss of heterozygosity of BRCA1 Associated Protein-1 (BAP1), a histone H2A lysine 119 deubiquitinase, occurs in over 25% of pancreatic cancer patients and shows a strong association with a history of chronic pancreatitis. Conditional deletion of Bap1 in murine pancreata led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance, even in heterozygous mice. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer arising from Mucinous Cystic Neoplasms (MCNs) and Intraductal Papillary Mucinous Neoplasms (IPMNs). Heterozygous mice also presented with advanced disease and compromised survival, suggesting a haploinsufficient tumor suppressor role for Bap1. Mechanistically, BAP1 maintains the integrity of the exocrine pancreas by regulating genomic stability, in a largely catalytic independent manner, and its loss in pancreatic cancer confers sensitivity to radio- and platinum-based therapies.