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Frequent Methylation-Associated Silencing of the Tissue Inhibitor of Metalloproteinase-3 Gene in Pancreatic Endocrine Tumors

Departments of Surgery (A.W., P.L., V.F., B.C., D.K.B.) and Pathology (A.R.), Institute of Theoretical Surgery (I.C.), and Department of Internal Medicine (B.S.), Philipps-University Marburg, 35043 Marburg, Germany

Address all correspondence and requests for reprints to: Detlef K. Bartsch, M.D., Department of Surgery, Philipps-University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. E-mail: bartsch{at}mailer.uni-marburg.de.

Molecular mechanisms contributing to the tumorigenesis of pancreatic endocrine tumors (PETs) are still not well understood. Allelic deletions at chromosome 22q12.3 were detected in about 30–60% of PETs, suggesting that inactivation of one or more tumor suppressor genes on this chromosomal arm is important for their pathogenesis. Because the putative tumor suppressor gene tissue inhibitor of metalloproteinase-3 (TIMP-3) has been located at 22q12.3, we undertook a genetic analysis of TIMP-3 to determine its role in the tumorigenesis of PETs. Single-strand conformational polymorphism analysis, methylation-specific PCR, RNA expression analysis, and immunohistochemistry of TIMP-3 were performed in 21 sporadic PETs. Thirteen of 21 PETs (62%) revealed TIMP-3 alterations, including promoter hypermethylation and homozygous deletion. The predominant TIMP-3 alteration was promoter hypermethylation, identified in 8 of 18 (44%) PETs. It was tumor-specific and corresponded to loss or strong reduction of TIMP-3 protein expression. Notably, 11 of 14 (79%) PETs with metastases had TIMP-3 alterations, compared with only 1 of 7 (14%) PETs without metastases (P < 0.02). These data suggest a possibly important role of TIMP-3 in the tumorigenesis of human PETs, especially in the development of metastases, which has to be further evaluated in large-scale studies.

This study was supported by the Deutsche Krebshilfe (Grant 10-1674-Ba I).

Abbreviations: LOH, Loss of heterozygosity; MMP, matrix metalloproteinases; MSP, methylation-specific PCR; NNPC, nonfunctioning neuroendocrine pancreatic carcinoma; PET, pancreatic endocrine tumor; SSCP, single-strand conformational polymorphism; TIMP-3, tissue inhibitor of metalloproteinase-3.

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