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.
Highlights
Chronic pancreatitis represents a risk factor for the development of pancreatic cancer
Heterozygous loss was accompanied by reduced transcript levels for several genes involved in DNA damage response (DDR) (Supplementary Fig. 1b), only BAP1 and RAD51C expression were significantly associated with lower risk and longer survival (Fig. 1b)
No correlation was found with the expression of PBRM1, a well-known tumor suppressor located in the same cytogenetic band as BAP1, as well as VHL, which is located on the short arm of chromosome 3 (Chr 3p25.3)
Summary
Chronic pancreatitis represents a risk factor for the development of pancreatic cancer. Improved survival has been reported for patients with mutations in DNA repair genes[4,6], the efficacy of FOLFIRINOX extends beyond the small percentage of cases exhibiting mutations of BRCA1/2, PALB2, and ATM, indicating that defects in other genes regulating the DDR may contribute as well. This observation motivated us to analyze pancreatic cancer genomes for copy number alterations (CNAs) of genes implicated in DNA repair. We find that genomic instability due to the loss of BAP1 is frequently observed in patients with pancreatic cancer and is associated with a history of chronic pancreatitis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
