KRAS2 Mutations in Human Pancreatic Acinar-Ductal Metaplastic Lesions Are Limited to Those with PanIN: Implications for the Human Pancreatic Cancer Cell of Origin

Abstract

Pancreatic intraepithelial neoplasia (PanIN) is a precursor to invasive ductal adenocarcinoma of the pancreas. Observations made in genetically engineered mouse models suggest that the acinar/centroacinar compartment can give rise to ductal neoplasia. To integrate findings in mice and men, we examined human acinar cells, acinar-ductal metaplasia (ADM) lesions, and PanINs for KRAS2 gene mutations. Surgically resected pancreata were screened for foci of ADM with or without an associated PanIN lesion. Stromal cells, acinar cells, ADMs, and PanINs were separately isolated using laser capture microdissection. KRAS2 status was analyzed using genomic DNA isolated from the microdissected tissue. Twelve of these 31 foci of ADM occurred in isolation, whereas 19 were in the same lobules as a PanIN lesion. All 31 microdissected foci of acinar cells were KRAS2 gene wild-type, as were all 12 isolated ADM lesions lacking an associated PanIN. KRAS2 gene mutations were present in 14 of 19 (74%) PanIN lesions and in 12 of the 19 (63%) foci of ADM associated with these PanINs. All ADM lesions with a KRAS2 gene mutation harbored the identical KRAS2 gene mutation found in their associated PanIN lesions. Ductal neoplasms of the human pancreas, as defined by KRAS2 gene mutations, do not appear to arise from acinar cells. Isolated AMD lesions are genetically distinct from those associated with PanINs, and the latter may represent retrograde extension of the neoplastic PanIN cells or less likely are precursors to PanIN.

Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

“…In contrast, the neoplastic transformation and disease progression observed in the pancreas of Pdx1-Cre;LSL-Kras G12D mice faithfully mimics the progression of human pancreatic ductal adenocarcinoma (PDA) through a series of precursor lesions known as pancreatic intraepithelial neoplasias (PanINs) (11,12). Moreover, not only is PDA among the human cancers most frequently associated with oncogenic mutations in the KRAS gene (13), but activating mutations in the KRAS proto-oncogene have been found in patients with early PanIN lesions (14), suggesting that KRAS mutations may be an initiating genetic event for PDA. We therefore sought to further investigate the role of ICMT in KRAS-driven cancer using the Pdx1-Cre;LSL-Kras G12D model of PDA.…”

RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies

“…Moreover, ectopic expression of KRAS 12D or KRAS 12C in TP53 knockdown human bronchial epithelial cells (HBECsiP53) had different effects on AKT activation and RalA/B expression [146], suggesting that different mutant alleles may have different preferences in activating downstream pathways. Consistent with the roles of Kras mutations in tumor initiation in mouse models, analysis of clinical specimens revealed that KRAS mutations are frequently detected in human hyperplastic/metaplastic pancreatic acinar-ductal cells [152][153][154] and colorectal adenomas [155][156][157]. KRAS alterations may represent an early event in pancreatic ductal tumorigenesis, whereas TP53 gene changes may represent an event required for the malignancy progression of ductal tumors from lower to higher grades [158].…”

Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma

“…In addition, the decrease in zinc, ZIP3 and RREB-1 in the acinar epithelium and in the ductal epithelium in early malignancy supports the view that ductal adenocarcinoma might involve the transdifferentiation of acini cells to a duct cell phenotype. [29][30][31] This might be represented in pancreatic intraepithelial neoplasia (the possible precursor lesion to ductal adenocarcinoma). Such a relationship exists for zinc and ZIP1 in prostate cancer.…”