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• W2040252009 abstract "An inactivating germline mutation in BRCA2 is the most common known genetic basis for familial pancreatic cancer (FPC), accounting for 5-10% of inherited cases. A genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) arising on the backdrop of Brca2 deficiency is likely to elucidate valuable diagnostic and therapeutic insights for FPC. Both Brca2 alleles were conditionally deleted during development within the pancreatic epithelium by generating Pdx1-Cre; Brca2f/f (“CB”) mice; in addition, triple transgenic Pdx1-Cre; Brca2f/f; LSL-Trp53R172H (“CBP”) mice were generated, in order to determine the impact of p53 deregulation on Brca2-deficient carcinogenesis. Both “CB” and “CBP” mice developed non-invasive ductal precursor lesions (murine pancreatic intraepithelial neoplasia or mPanIN), although these were observed at an earlier time point (5 versus 8 months) and with higher prevalence in “CBP” mice. A minority of “CB” mice (15%) developed invasive and metastatic PDAC at a latency of 15 months or greater; in contrast, “CBP” mice of comparable age uniformly developed PDAC with variable histological features. Mortality in the absence of neoplasia in CB and CBP mice was associated with profound loss of pancreatic parenchyma, consistent with progressive elimination of Brca2-deficient cells. Widespread DNA damage, as evidenced by overexpression of the phosphorylated histone H2AXSer139, was observed in the non-neoplastic exocrine pancreas, as well as in the mPanIN and PDAC lesions of Brca2-deficient mice, independent of p53 status. Loss of Brca2 function predisposes the exocrine pancreas to profound DNA damage, and the frequency of invasive neoplasia is accentuated by the concomitant deregulation of p53.See commentary:Brca2 deficiency and Trp53 deregulation in pancreatic cancer: Implications for therapeutic targeting" @default.
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• W2040252009 date "2011-06-01" @default.
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• W2040252009 title "Inactivation of<i>Brca2</i>cooperates with<i>Trp53</i>^R172Hto induce invasive pancreatic ductal adenocarcinomas in mice" @default.
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• W2040252009 doi "https://doi.org/10.4161/cbt.11.11.15534" @default.
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