Overexpression of p21 Is a Marker of Tumor Metastasis in Primary Pancreatic Neuroendcrine Neoplasms
NA Hafez, L Turner, EB Henderson-Jackson, NA Nasir, J Strosberg, J Helm, MM Bui, D Coppola, A Hakam, L Kvols, MP Malafa, A Nasir. Moffitt Cancer Center, Tampa, FL
Background: p21 is an inhibitor of cyclin-dependent kinases and is down-regulated by p53 to inactivate cell proliferation. Some studies have failed to demonstrate a correlation between p21 expression and the status of p53 gene in cancer suggesting that p21 might also be regulated by p53-independent pathways. Using an Affymetrix platform, we identified p21 as one of the leading metastasis-associated genes in primary pancreatic endocrine carcinomas (PECAs) that had already metastasized to the liver. Expression of p21 has not been studied in metastatic PECAs and non-metastatic primary pancreatic endocrine tumors (NMP-PETs).
Design: To elucidate the expression of p21 gene product in MP-PECAs, NMP-PETs, and normal pancreatic islets, we constructed Tissue Microarrays (TMAs) from archival tumor blocks. In order to study the phenotypic/genotypic heterogeneity of the tumors and their relation to normal islets, 5 tumor cores and up to 5 adjacent pancreatic tissue cores with islets (as tissue controls) were selected for each case. The 65 cases in the TMAs included 22 MP-PECAs, 35 NMP-PETs and 8 cases of poorly differentiated neuroendocrine carcinoma (PD-NECAs) of the lung and other sites. Standard Avidin-Biotin IHC techniques were used to stain TMAs for p21 (WAF1, CIP) antibody (Calbiochem-Oncogen). Based on evaluation of all cores in the TMA, a p21 index was calculated as percentageage (%) of the stained cells.
Results: Only nuclear staining was considered positive result. Percentages and ranges of positively stained nuclei (PN) were calculated for all 4 types of specimens as shown in Table 1.
Table 1: Results of nuclear staining
|Number of cases||20 (8 M/12 NM)||18||19||8|
|Range of PN||6-21||1-25||3-63||2-80|
|Average of PN||11||9||21||34|
The mean p21 expression index (%) for MP-PECAs was 21.0 vs. 8.72 for NMP-PETs (p=0.01). The mean p21 expression index (%) for all (both metastatic and non-metastatic) neoplasms vs. matched control islets was 14.8 vs. 7.9 (p=0.04).
Conclusions: We have validated p21 protein expression as a marker of metastatic phenotype in pancreatic endocrine tumors. High nuclear expression of p21 appears to have a potential clinical utility as a marker of tumor progression.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 92, Tuesday Afternoon