Pancreatic endocrine tumors occur sporadically and as part of the multiple 
endocrine neoplasia type 1 (MEN 1) and von Hippel-Lindau (VHL) syndromes. The 
MEN1 locus on 11q13 and a candidate tumor suppressor locus on 3p are known to be 
hemi- or homozygously mutated in a subset of these tumors. Chromosome arm 18q 
harbors the SMAD4/DPC4 tumor suppressor gene that is frequently deleted and 
inactivated in tumors of the exocrine pancreas. We have analyzed 22 nonfamilial 
and 16 MEN 1-associated pancreatic endocrine tumors for loss of heterozygosity 
(LOH) at 3p, 11q13, and 18q. LOH at 3p was revealed in 45% and 36% of tumors 
from 31 patients with nonfamilial and MEN 1-associated disease, respectively. 
The corresponding proportions for 11q13 were 55% and 91%, and for 18q 27% and 
25%, respectively. A striking relation between LOH at 11q13 and 3p and a 
malignant phenotype was found for the nonfamilial tumors. None of the six benign 
tumors (all of them insulinomas) had allelic loss at 3p or 11q13, whereas 92% (P 
< 0.01) of the malignant tumors (including malignant insulinomas) had such 
deletions. Besides the 11q13 abnormality, more than half of the MEN 1-associated 
tumors had additional genetic lesions affecting 3p or 18q. LOH analysis of 
several tumors from two MEN 1 patients suggested different clonal origin of the 
lesions. Sequencing of the SMAD4/DPC4 gene did not identify mutations in coding 
regions or at exon/intron boundaries in tumors with LOH at 18q. The data 
indicate involvement of tumor suppressor genes on 3p and 18q, in addition to the 
MEN1 gene at 11q13, in the tumorigenesis of both nonfamilial and MEN 
1-associated pancreatic endocrine tumors.