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ActivatingKRAS mutations andp16Ink4a inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, KrasG12D initiates formation of premalignant pancreatic ductal lesions, and loss of eitherInk4a /Arf (p16Ink4a /p19Arf ) orp53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role forp16Ink4a in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of p16Ink4a , p19Arf , and/or p53 in the KrasG12D model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of eitherp53 orp16Ink4a , the latter with intact germ-line p53 andp19Arf sequences. Additionally, KrasG12D in the context of heterozygosity either forp53 plusp16Ink4a or forp16Ink4a /p19Arf produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion ofp53 orp16Ink4a /p19Arf . Tumors from the double-heterozygous cohorts showed frequent p16Ink4a inactivation and loss of either p53 or p19Arf . Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygousp16Ink4a /p19Arf mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16Ink4a and the p19ARF -p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.

Both p16 Ink4a and the p19 Arf -p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse

Both p16 ^Ink4a and the p19 ^Arf -p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse