Genotype/phenotype correlation of multiple endocrine neoplasia type 1 genemutations in sporadic gastrinomas

Multiple endocrine neoplasia type 1 (MEN1) gene mutations are reported in s ome 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 manife stations. The purpose of the present study was to correlate mutations of th e MEN1 gene in a large cohort of patients with sporadic gastrinomas to dise ase activity, tumor location, extent, and growth pattern. DNA was extracted from frozen gastrinomas from 51 patients and screened by dideoxyfingerprin ting (ddF) for abnormalities in the 9 coding exons and adjacent splice junc tions of the MEN1 gene. Tumor DNA exhibiting abnormal ddF patterns was sequ enced for mutations. The findings were correlated with clinical manifestati ons of the disease, primary tumor site, disease extent, and tumor growth po stoperatively. Tumor growth was determined by serial imaging studies. Sixte en different MEN1 gene mutations in the 51 sporadic gastrinomas (31%) were identified (11 truncating, 4 missense, and 1 in-frame deletion). Nine of th e 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 mutati on (P = 0.02). There was no difference between patients with or without a m utation with respect to clinical characteristics, primary tumor site, disea se extent, or proportion of patients disease free after surgery. Postoperat ive tumor growth tended to be more aggressive inpatients with a mutation (P = 0.09). No correlation in the rate of disease-free status or postoperativ e tumor growth in patients with active disease to the location of the mutat ion 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, gastr inoma extent, or growth pattern; however, the location of the mutation diff ered with gastrinoma location. These data suggest that mutations in the MEN 1 gene are important in a proportion of sporadic gastrinomas, but the prese nce or absence of these mutations will not identify the clinically importan t subgroups with different growth patterns.