K-ras, p53, and DPC4 (MAD4) alterations in fine-needle aspirates of the pancreas: a molecular panel correlates with and supplements cytologic diagnosis

Between January 1997 and February 2000, 101 fine-needle pancreatic aspirates were obtained. After a cytologic diagnosis was made, possible molecular alterations were determined on the 94 aspirates with adequate tissue using a molecular panel (K-ras, p53, and DPC4 [MAD4] genes). The 94 aspirates were categorized as follows: diagnostic of adenocarcinoma, 48 (51%); atypical (suggestive of but not diagnostic of adenocarcinoma), 19 (20%); negative for adenocarcinoma, 25 (2 7%); diagnostic of a neoplasm other than adenocarcinoma, 2 (2%). Clinical follow-up revealed that 3 patients (12%) with negative cytologic diagnoses and 12 patients (63%) with atypical cytologic diagnoses had adenocarcinoma. Of 63 with a final diagnosis of adenocarcinoma, 42 (67%) had an alteration in at least 1 of the genes analyzed. In contrast, only 2 (6%) of 31 patients without adenocarcinoma had an alteration in 1 gene on the panel. Overall, the molecular analyses supported the diagnosis of adenocarcinoma in 6 (32%) of 19 aspirates originally diagnosed as atypical by cytology alone. A molecular panel that includes the K-ras, p53, and DPC4 (MAD4) genes correlates with and can supplement traditional cytologic diagnosis of pancreatic fine-needle aspirate

Aberrant methylation of preproenkephalin and p16 genes in pancreatic Intraepithelial neoplasia and pancreatic ductal adenocarcinoma

Pancreatic intraductal neoplasia (PanIN) is thought to be the precursor to infiltrating pancreatic ductal adenocarcinoma. We have previously shown that the preproenkephalin (ppENK) and p16 genes are aberrantly methylated in pancreatic adenocarcinoma. In this study we define the methylation status of the ppENK and p16 genes in various grades of PanINs. One hundred seventy-four samples (28 nonneoplastic pancreatic epithelia, 7 reactive epithelia, 29 PanIN-1A, 48 PanIN-1B, 27 PanIN-2, 14 PanIN-3, 15 invasive ductal adenocarcinomas, and 6 miscellaneous pancreatic neoplasms) were microdissected from 29 formalin-fixed paraffin-embedded surgically resected pancreata, and were analyzed by methylation-specific polymerase chain reaction. Fourteen of 15 (93.3%) invasive pancreatic ductal adenocarcinomas showed methylation of the ppENK gene and 4 of 15 (26.7%) showed methylation of the p16 gene. Nonneoplastic pancreatic epithelia did not harbor methylation of either gene. The prevalence of methylation of the ppENK gene increased significantly with increasing PanIN grade. A similar nonsignificant trend was noted for p16 methylation. Aberrant methylation of the ppENK gene was found in 7.7% of PanIN-1A, 7.3% of PanIN-1B, 22.7% of PanIN-2, and 46.2% of PanIN-3. Aberrant methylation of the p16 gene was found in 12% of PanIN-1A, 2.6% of PanIN-1B, 4.5% of PanIN-2, and 21.4% of PanIN-3. All but one of the PanINs from the 14 pancreata without pancreatic carcinoma was unmethylated with respect to either the p16 or ppENK gene. Our results suggest that methylation-related inactivation of the ppENK and p16 genes is an intermediate or late event during pancreatic carcinogenesis. Because aberrant methylation of ppENK or p16 was more often detected in similar grade PanINs from patients with pancreatic carcinoma than in those with other pancreatic diseases, it may be a useful indicator of the potential malignancy of epithelial cells of the pancreas

Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: Identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE)

Purpose: Effective new markers of pancreatic carcinoma are urgently needed. In a previous analysis of gene expression in pancreatic adenocarcinoma using serial analysis of gene expression (SAGE), we found that the tag for the mesothelin mRNA transcript was present in seven of eight SAGE libraries derived from pancreatic carcinomas but not in the two SAGE libraries derived from normal pancreatic duct epithelial cells. In this study, we evaluate the potential utility of mesothelin as a tumor marker for pancreatic adenocarcinoma

The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma

Purpose: SMAD4 (also called Dpc4) is a tumor suppressor in the TGF-beta signaling(1) pathway that is genetically inactivated in similar to 55% of all pancreatic adenocarcinomas. We investigated whether prognosis after surgical resection for invasive pancreatic adenocarcinoma is influenced by SMAD4 status