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Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas.
J Clin Endocrinol Metab. 2000 Jan; 85(1):116-23.JC

Abstract

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 dideoxyfinger-printing (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.

Authors+Show Affiliations

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1804, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

10634374

Citation

Goebel, S U., et al. "Genotype/phenotype Correlation of Multiple Endocrine Neoplasia Type 1 Gene Mutations in Sporadic Gastrinomas." The Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 1, 2000, pp. 116-23.
Goebel SU, Heppner C, Burns AL, et al. Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas. J Clin Endocrinol Metab. 2000;85(1):116-23.
Goebel, S. U., Heppner, C., Burns, A. L., Marx, S. J., Spiegel, A. M., Zhuang, Z., Lubensky, I. A., Gibril, F., Jensen, R. T., & Serrano, J. (2000). Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas. The Journal of Clinical Endocrinology and Metabolism, 85(1), 116-23.
Goebel SU, et al. Genotype/phenotype Correlation of Multiple Endocrine Neoplasia Type 1 Gene Mutations in Sporadic Gastrinomas. J Clin Endocrinol Metab. 2000;85(1):116-23. PubMed PMID: 10634374.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas. AU - Goebel,S U, AU - Heppner,C, AU - Burns,A L, AU - Marx,S J, AU - Spiegel,A M, AU - Zhuang,Z, AU - Lubensky,I A, AU - Gibril,F, AU - Jensen,R T, AU - Serrano,J, PY - 2000/1/14/pubmed PY - 2000/1/14/medline PY - 2000/1/14/entrez SP - 116 EP - 23 JF - The Journal of clinical endocrinology and metabolism JO - J Clin Endocrinol Metab VL - 85 IS - 1 N2 - 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 dideoxyfinger-printing (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. SN - 0021-972X UR - https://www.unboundmedicine.com/medline/citation/10634374/Genotype/phenotype_correlation_of_multiple_endocrine_neoplasia_type_1_gene_mutations_in_sporadic_gastrinomas_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jcem.85.1.6260 DB - PRIME DP - Unbound Medicine ER -