This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Muscarella, P. Articles by Weghorst, C. M. Search for Related Content PubMed Articles by Muscarella, P. Articles by Weghorst, C. M.

Genetic Alterations in Gastrinomas and Nonfunctioning Pancreatic Neuroendocrine Tumors: An Analysis of p16/MTS1 Tumor Suppressor Gene Inactivation¹

Divisions of General Surgery [P. M., W. S. M., W. E. F., J. F., W. J. S., E. C. E.] and Environmental Health Sciences [C. M. W.], Department of Pathology [C. L. H., B. R. D.], College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210-1240, and The Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2195 [J. G. H.]

Neoplasms of the endocrine pancreas are extremely rare, and molecular mechanisms influencing their development are poorly understood. Nevertheless, gastrinomas have become a paradigm for the study of hormonally active tumors. In the present study, 12 gastrinoma and nonfunctioning pancreatic neuroendocrine tumor specimens were evaluated for genetic alterations of the p16/MTS1 tumor suppressor gene. DNA extracted from microdissected portions of paraffin-embedded tumor sections were examined for mutations and homozygous deletions using "Cold" single-strand conformation polymorphism and semiquantitative PCR-based analyses, respectively. Samples were also analyzed for the presence of 5' CpG island hypermethylation using methylation-specific PCR. The p16/MTS1 gene was found to be homozygously deleted in 41.7% of tumors and methylated in 58.3%, but no mutations were identified by single-strand conformation polymorphism analyses. Overall, 91.7% of the specimens demonstrated inactivating alterations in p16/MTS1. These data suggest that transcriptional silencing of p16/MTS1 is a frequent event in these rare and poorly understood tumors.

¹ This investigation was supported by the National Cancer Institute, National Research Service Award CA-09338, Division of Cancer Prevention and Control. Other funding was supplied by grants from the Ohio Division of the American Cancer Society and the Bremer Foundation at The Ohio State University. J. G. H. receives research funding and is entitled to sales royalties from ONCOR, which is developing products related to research described in this paper. The terms of this arrangement have been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.

² To whom requests for reprints should be addressed, at The Ohio State University, 300 West 10th Avenue, CHRI: 1148, Columbus, OH 43210-1240.

Received 10/10/97. Accepted 12/ 1/97.

This article has been cited by other articles:

				E.-M. Duerr, Y. Mizukami, A. Ng, R. J Xavier, H. Kikuchi, V. Deshpande, A. L Warshaw, J. Glickman, M. H Kulke, and D. C Chung Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis Endocr. Relat. Cancer, March 1, 2008; 15(1): 243 - 256. [Abstract] [Full Text] [PDF]

				T. M. Katona, T. D. Jones, M. Wang, F. W. Abdul-Karim, O. W. Cummings, and L. Cheng Molecular Evidence for Independent Origin of Multifocal Neuroendocrine Tumors of the Enteropancreatic Axis. Cancer Res., May 1, 2006; 66(9): 4936 - 4942. [Abstract] [Full Text] [PDF]

				J. Li, C. M. Weghorst, M. Tsutsumi, M. J. Poi, T. J. Knobloch, B. C. Casto, W. S. Melvin, M.-D. Tsai, and P. Muscarella Frequent p16INK4A/CDKN2A alterations in chemically induced Syrian golden hamster pancreatic tumors Carcinogenesis, February 1, 2004; 25(2): 263 - 268. [Abstract] [Full Text] [PDF]

				D. Furlan, R. Cerutti, S. Uccella, S. La Rosa, E. Rigoli, A. Genasetti, and C. Capella Different Molecular Profiles Characterize Well-Differentiated Endocrine Tumors and Poorly Differentiated Endocrine Carcinomas of the Gastroenteropancreatic Tract Clin. Cancer Res., February 1, 2004; 10(3): 947 - 957. [Abstract] [Full Text] [PDF]

				A. Wild, A. Ramaswamy, P. Langer, I. Celik, V. Fendrich, B. Chaloupka, B. Simon, and D. K. Bartsch Frequent Methylation-Associated Silencing of the Tissue Inhibitor of Metalloproteinase-3 Gene in Pancreatic Endocrine Tumors J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1367 - 1373. [Abstract] [Full Text] [PDF]

				Y.-J. Chen, A. Vortmeyer, Z. Zhuang, S. Huang, and R. T. Jensen Loss of Heterozygosity of Chromosome 1q in Gastrinomas: Occurrence and Prognostic Significance Cancer Res., February 15, 2003; 63(4): 817 - 823. [Abstract] [Full Text] [PDF]

				S. U. Goebel, M. Iwamoto, M. Raffeld, F. Gibril, W. Hou, J. Serrano, and R. T. Jensen HER-2/neu Expression and Gene Amplification in Gastrinomas: Correlations with Tumor Biology, Growth, and Aggressiveness Cancer Res., July 1, 2002; 62(13): 3702 - 3710. [Abstract] [Full Text] [PDF]

				P. L. Peghini, M. Iwamoto, M. Raffeld, Y.-J. Chen, S. U. Goebel, J. Serrano, and R. T. Jensen Overexpression of Epidermal Growth Factor and Hepatocyte Growth Factor Receptors in a Proportion of Gastrinomas Correlates with Aggressive Growth and Lower Curability Clin. Cancer Res., July 1, 2002; 8(7): 2273 - 2285. [Abstract] [Full Text] [PDF]

				N. Lubomierski, M. Kersting, T. Bert, K. Muench, U. Wulbrand, M. Schuermann, D. Bartsch, and B. Simon Tumor Suppressor Genes in the 9p21 Gene Cluster Are Selective Targets of Inactivation in Neuroendocrine Gastroenteropancreatic Tumors Cancer Res., August 1, 2001; 61(15): 5905 - 5910. [Abstract] [Full Text] [PDF]

				E. J. M. Speel, A. F. Scheidweiler, J. Zhao, C. Matter, P. Saremaslani, J. Roth, P. U. Heitz, and P. Komminoth Genetic Evidence for Early Divergence of Small Functioning and Nonfunctioning Endocrine Pancreatic Tumors: Gain of 9Q34 Is an Early Event in Insulinomas Cancer Res., July 1, 2001; 61(13): 5186 - 5192. [Abstract] [Full Text] [PDF]

				H Tonnies, M R Toliat, C Ramel, U F Pape, H Neitzel, W Berger, and B Wiedenmann Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation Gut, April 1, 2001; 48(4): 536 - 541. [Abstract] [Full Text] [PDF]

				J. Serrano, S. U. Goebel, P. L. Peghini, I. A. Lubensky, F. Gibril, and R. T. Jensen Alterations in the p16INK4a/CDKN2A Tumor Suppressor Gene in Gastrinomas J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4146 - 4156. [Abstract] [Full Text]

				D. C. Chung, S. B. Brown, F. Graeme-Cook, M. Seto, A. L. Warshaw, R. T. Jensen, and A. Arnold Overexpression of Cyclin D1 Occurs Frequently in Human Pancreatic Endocrine Tumors J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4373 - 4378. [Abstract] [Full Text]

				F. Yu, R. T. Jensen, I. A. Lubensky, E. H. Mahlamaki, Y.-L. Zheng, A. M. Herr, and L. J. Ferrin Survey of Genetic Alterations in Gastrinomas Cancer Res., October 1, 2000; 60(19): 5536 - 5542. [Abstract] [Full Text]

				S. U. Goebel, C. Heppner, A. L. Burns, S. J. Marx, A. M. Spiegel, Z. Zhuang, I. A. Lubensky, F. Gibril, R. T. Jensen, and J. Serrano Genotype/Phenotype Correlation of Multiple Endocrine Neoplasia Type 1 Gene Mutations in Sporadic Gastrinomas J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 116 - 123. [Abstract] [Full Text]

				H. B. Salvesen, S. Das, and L. A. Akslen Loss of Nuclear p16 Protein Expression Is Not Associated with Promoter Methylation but Defines a Subgroup of Aggressive Endometrial Carcinomas with Poor Prognosis Clin. Cancer Res., January 1, 2000; 6(1): 153 - 159. [Abstract] [Full Text]

				E. J. M. Speel, J. Richter, H. Moch, C. Egenter, P. Saremaslani, K. Rutimann, J. Zhao, A. Barghorn, J. Roth, P. U. Heitz, et al. Genetic Differences in Endocrine Pancreatic Tumor Subtypes Detected by Comparative Genomic Hybridization Am. J. Pathol., December 1, 1999; 155(6): 1787 - 1794. [Abstract] [Full Text] [PDF]