Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome

William G Dilley,Sulekha Verma,Jason M Laramie,Terry C Lairmore,Somasundaram Kalyanaraman,J Perren Cobb

doi:10.1186/1476-4598-4-9

William G Dilley, Sulekha Verma + Show 4 more

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https://doi.org/10.1186/1476-4598-4-9

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Journal: Molecular Cancer	Publication Date: Jan 1, 2005
Citations: 131	License type: cc-by

Affiliation: John Cochran VA Medical Center

Abstract

BackgroundMultiple Endocrine Neoplasia type 1 (MEN1, OMIM 131100) is an autosomal dominant disorder characterized by endocrine tumors of the parathyroids, pancreatic islets and pituitary. The disease is caused by the functional loss of the tumor suppressor protein menin, coded by the MEN1 gene. The protein sequence has no significant homology to known consensus motifs. In vitro studies have shown menin binding to JunD, Pem, Smad3, NF-kappaB, nm23H1, and RPA2 proteins. However, none of these binding studies have led to a convincing theory of how loss-of-menin leads to neoplasia.ResultsGlobal gene expression studies on eight neuroendocrine tumors from MEN1 patients and 4 normal islet controls was performed utilizing Affymetrix U95Av2 chips. Overall hierarchical clustering placed all tumors in one group separate from the group of normal islets. Within the group of tumors, those of the same type were mostly clustered together. The clustering analysis also revealed 19 apoptosis-related genes that were under-expressed in the group of tumors. There were 193 genes that were increased/decreased by at least 2-fold in the tumors relative to the normal islets and that had a t-test significance value of p < = 0.005. Forty-five of these genes were increased and 148 were decreased in the tumors relative to the controls. One hundred and four of the genes could be classified as being involved in cell growth, cell death, or signal transduction. The results from 11 genes were selected for validation by quantitative RT-PCR. The average correlation coefficient was 0.655 (range 0.235–0.964).ConclusionThis is the first analysis of global gene expression in MEN1-associated neuroendocrine tumors. Many genes were identified which were differentially expressed in neuroendocrine tumors arising in patients with the MEN1 syndrome, as compared with normal human islet cells. The expression of a group of apoptosis-related genes was significantly suppressed, suggesting that these genes may play crucial roles in tumorigenesis in this syndrome. We identified a number of genes which are attractive candidates for further investigation into the mechanisms by which menin loss causes tumors in pancreatic islets. Of particular interest are: FGF9 which may stimulate the growth of prostate cancer, brain cancer and endometrium; and IER3 (IEX-1), PHLDA2 (TSS3), IAPP (amylin), and SST, all of which may play roles in apoptosis.

Highlights

Multiple Endocrine Neoplasia type 1 (MEN1, OMIM 131100) is an autosomal dominant disorder characterized by endocrine tumors of parathyroid, pancreatic islets and pituitary [1]
Patients and Controls Eight neuroendocrine tumors from six MEN1 patients were included in this study
XRCC4, a gene involved in doublestrand break repair, was decreased in the tumors in the current study. This first study of global gene expression in neuroendocrine tumors arising in the pancreas of patients with the MEN1 syndrome has identified many genes that are differentially expressed, as compared with normal human islet cells

Summary

Introduction

Multiple Endocrine Neoplasia type 1 (MEN1, OMIM 131100) is an autosomal dominant disorder characterized by endocrine tumors of the parathyroids, pancreatic islets and pituitary. The disease is caused by the functional loss of the tumor suppressor protein menin, coded by the MEN1 gene. The protein sequence has no significant homology to known consensus motifs. In vitro studies have shown menin binding to JunD, Pem, Smad, NF-kappaB, nm23H1, and RPA2 proteins. None of these binding studies have led to a convincing theory of how loss-ofmenin leads to neoplasia. Five new germline mutations which affect splicing of premRNA transcribed from MEN1 gene were identified in our laboratory [6]. The nature of all the disease-inducing mutations points to a loss of function of menin, which is characteristic of a tumor suppressor. Database analysis of menin protein sequence reveals no significant homology to known consensus protein motifs. Menin is primarily localized in the nucleus and contains two nuclear localization signal sequences near the carboxyl terminus of the protein [7]

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