2005 Abstracts: Genetic Differentiation of Neuroendocrine and Adenocarcinoid Appendiceal Tumors
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Genetic Differentiation of Neuroendocrine and Adenocarcinoid Appendiceal Tumors
Irvin M. Modlin, Igor Latic, Mark Kidd, Shrikant Mane, Yale University School of Medicine, New Haven, CT
Introduction:
Appendiceal enterochromaffin cell (EC) carcinoids are among the most common carcinoids but are usually only identified postoperatively. Thereafter, considerable controversy often exists in regard to appropriate surgical management (re-operation) since it is difficult to predict or define tumor behavior and only arbitrary criteria (size, location, mitotic number) exist to define this decision. Utilizing global GeneChip analysis of small intestinal EC carcinoids and their metastases we have identified four differentially expressed genes (the mitosis-regulatory gene NAP1L1; the adhesin MAGE-D2, the estrogen-antagonist MTA1 and the apoptotic marker NALP1) from a base of 1,550 genes. We propose that these genes can discriminate “benign” neuroendocrine (NE) EC carcinoids from malignant varieties and mixed cell NE appendiceal adenocarcinoid tumors. Methods: Total RNA was isolated using TRIzol reagent from 25 appendiceal tumors including EC carcinoids (<1cm in size, no evidence of metastasis; n=20) and mixed (goblet) cell appendiceal adenocarcinoids (>1.5cm, evidence of metastatic invasion; n=5) and normal appendiceal tissue (n=10). Gene expression (NAP1L1, MAGE-D2, MTA1 and NALP1) was examined by Q-RT PCR (Applied Biosystems) and quantified against GAPDH. Results: Message levels of NAP1L1 were elevated (>5-fold, p<0.05) only in malignant appendiceal adenocarcinoids. MAGE-D2 message was also significantly elevated (>20-fold, p<0.03), as was message from the MTA1 gene (>12-fold, p<0.03), in the malignant adenocarcinoids but not in the NE appendiceal carcinoids or normal mucosa. The apoptotic marker, NALP1, was over-expressed (>80-fold, p<0.02) in the NE appendiceal carcinoids, but was significantly decreased (>10-fold, p<0.05) in malignant appendiceal adenocarcinoids. Conclusion: These data demonstrate that malignant appendiceal adenocarcinoids, which are a mixed NE EC tumor type, have elevated expression of NAP1L1, MAGE-D2 and MTA1 compared to NE appendiceal carcinoids which do not metastasize. This information and the differences in NALP1 gene expression (elevated in NE appendiceal carcinoids, decreased in malignant adenocarcinoids), provides a series of molecular signatures to differentiate between malignant and non-malignant carcinoids of the appendix. This molecular delineation of malignant appendiceal tumor potential provides a scientific basis to define the appropriate surgical management (particularly extent of surgery) of these lesions.
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