This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goebel, S. U. Articles by Serrano, J. Search for Related Content PubMed PubMed Citation Articles by Goebel, S. U. Articles by Serrano, J. Pubmed/NCBI databases Genetics Home Reference Medline Plus Health Information Pancreatic Cancer

Genotype/Phenotype Correlation of Multiple Endocrine Neoplasia Type 1 Gene Mutations in Sporadic Gastrinomas

Digestive Diseases Branch (S.U.G., F.G., R.T.J., J.S.) and the Metabolic Diseases Branch (C.H., A.L.B., S.J.M., A.M.S.), National Institute of Diabetes and Digestive and Kidney Diseases, and the Laboratory of Pathology, National Cancer Institute (Z.Z., I.A.L.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Robert T. Jensen, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9C-103, 10 Center Drive, MSC 1804, Bethesda, Maryland 20892-1804.

Multiple endocrine neoplasia type 1 (MEN1) gene mutations are reported in some gastrinomas occurring in patients without MEN1 as well as in some other pancreatic endocrine tumors (PETs). In some inherited syndromes phenotype-genotype correlations exist for disease severity, location, or other manifestations. The purpose of the present study was to correlate mutations of the MEN1 gene in a large cohort of patients with sporadic gastrinomas to disease activity, tumor location, extent, and growth pattern. DNA was extracted from frozen gastrinomas from 51 patients and screened by dideoxyfingerprinting (ddF) for abnormalities in the 9 coding exons and adjacent splice junctions of the MEN1 gene. Tumor DNA exhibiting abnormal ddF patterns was sequenced for mutations. The findings were correlated with clinical manifestations of the disease, primary tumor site, disease extent, and tumor growth postoperatively. Tumor growth was determined by serial imaging studies. Sixteen different MEN1 gene mutations in the 51 sporadic gastrinomas (31%) were identified (11 truncating, 4 missense, and 1 in-frame deletion). Nine of the 16 mutations were located in exon 2 compared to 7 of 16 in the remaining 8 coding exons (P = 0.005 on a per nucleotide basis). Primary pancreatic or lymph node gastrinomas with a mutation had only exon 2 mutations, whereas duodenal tumors uncommonly harbored exon 2 mutations (P = 0.011). Similarly, small primary tumors (<1 cm) more frequently contained a nonexon 2 mutation (P = 0.02). There was no difference between patients with or without a mutation with respect to clinical characteristics, primary tumor site, disease extent, or proportion of patients disease free after surgery. Postoperative tumor growth tended to be more aggressive in patients with a mutation (P = 0.09). No correlation in the rate of disease-free status or postoperative tumor growth in patients with active disease to the location of the mutation was seen. These results demonstrate that the MEN1 gene is mutated in 31% of sporadic gastrinomas, and mutations are clustered between amino acids 66–166, which differs from patients with familial MEN1, in whom mutations occur throughout the gene. The presence of an MEN1 gene mutation does not correlate with clinical characteristics of patients with gastrinomas, gastrinoma extent, or growth pattern; however, the location of the mutation differed with gastrinoma location. These data suggest that mutations in the MEN1 gene are important in a proportion of sporadic gastrinomas, but the presence or absence of these mutations will not identify the clinically important subgroups with different growth patterns.

This article has been cited by other articles:

				O Vierimaa, T M L Ebeling, S Kytola, R Bloigu, E Eloranta, J Salmi, E Korpi-Hyovalti, L Niskanen, A Orvola, E Elovaara, et al. Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation Eur. J. Endocrinol., September 1, 2007; 157(3): 285 - 294. [Abstract] [Full Text] [PDF]

				M. Furukawa, M. Raffeld, C. Mateo, A. Sakamoto, T. W. Moody, T. Ito, D. J. Venzon, J. Serrano, and R. T. Jensen Increased Expression of Insulin-Like Growth Factor I and/or Its Receptor in Gastrinomas Is Associated with Low Curability, Increased Growth, and Development of Metastases Clin. Cancer Res., May 1, 2005; 11(9): 3233 - 3242. [Abstract] [Full Text] [PDF]

				J W Cardinal, L Bergman, N Hayward, A Sweet, J Warner, L Marks, D Learoyd, T Dwight, B Robinson, M Epstein, et al. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing J. Med. Genet., January 1, 2005; 42(1): 69 - 74. [Abstract] [Full Text] [PDF]

				B. Asgharian, M. L. Turner, F. Gibril, L. K. Entsuah, J. Serrano, and R. T. Jensen Cutaneous Tumors in Patients with Multiple Endocrine Neoplasm Type 1 (MEN1) and Gastrinomas: Prospective Study of Frequency and Development of Criteria with High Sensitivity and Specificity for MEN1 J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5328 - 5336. [Abstract] [Full Text] [PDF]

				W. Hao, M. C. Skarulis, W. F. Simonds, L. S. Weinstein, S. K. Agarwal, C. Mateo, L. James-Newton, G. R. Hobbs, F. Gibril, R. T. Jensen, et al. Multiple Endocrine Neoplasia Type 1 Variant with Frequent Prolactinoma and Rare Gastrinoma J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3776 - 3784. [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]

				I. Cavallari, D. M. D'Agostino, T. Ferro, A. Rosato, L. Barzon, C. Pasquali, P. Fogar, M. Theodoropoulou, G. Esposito, M. Boscaro, et al. In Situ Analysis of Human Menin in Normal and Neoplastic Pancreatic Tissues: Evidence for Differential Expression in Exocrine and Endocrine Cells J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3893 - 3901. [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]

				S. J. Marx and L. K. Nieman Aggressive Pituitary Tumors in MEN1: Do They Refute the Two-Hit Model of Tumorigenesis? J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 453 - 456. [Full Text] [PDF]

				M. L. Brandi, R. F. Gagel, A. Angeli, J. P. Bilezikian, P. Beck-Peccoz, C. Bordi, B. Conte-Devolx, A. Falchetti, R. G. Gheri, A. Libroia, et al. CONSENSUS: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2 J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5658 - 5671. [Abstract] [Full Text] [PDF]

				S. S. Guo and M. P. Sawicki Molecular and Genetic Mechanisms of Tumorigenesis in Multiple Endocrine Neoplasia Type-1 Mol. Endocrinol., October 1, 2001; 15(10): 1653 - 1664. [Abstract] [Full Text] [PDF]

				C. A. Stratakis, D. H. Schussheim, S. M. Freedman, M. F. Keil, S. D. Pack, S. K. Agarwal, M. C. Skarulis, R. J. Weil, I. A. Lubensky, Z. Zhuang, et al. Pituitary Macroadenoma in a 5-Year-Old: An Early Expression of Multiple Endocrine Neoplasia Type 1 J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4776 - 4780. [Abstract] [Full Text]

				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]

				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]