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

• Published in: The journal of clinical endocrinology and metabolism 2000-01, Vol.85 (1), p.116-123
• Main Authors: Goebel, Stephan U., Heppner, Christina, Burns, A. Lee, Marx, Stephen J., Spiegel, Allen M., Zhuang, Zhengping, Lubensky, Irina A., Gibril, Fathia, Jensen, Robert T., Serrano, José
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological and medical sciences; DNA, Neoplasm - analysis; DNA, Neoplasm - genetics; Exons - genetics; Female; Gastrinoma - genetics; Gastroenterology. Liver. Pancreas. Abdomen; Genotype; Humans; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Multiple Endocrine Neoplasia Type 1 - genetics; Mutation - genetics; Pancreatic Neoplasms - genetics; Phenotype; Polymerase Chain Reaction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Zollinger-Ellison Syndrome - genetics
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jcem.85.1.6260

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 (