Frequent loss of heterozygosity at chromosome 3p14.2-3p21 in human pancreatic islet cell tumours.
OBJECTIVE
Pancreatic islet betacell tumours occur either sporadically or as part of inherited neoplastic syndromes, most commonly multiple endocrine neoplasia (MEN) type 1. Recently, a transgenic mouse model has been established in which the expression of the SV40 large T antigen was targeted to betacells by the rat insulin promoter, leading to the development of multiple pancreatic betacell tumours. In the advanced stages of tumour evolution, these tumours exhibited a high prevalence of loss of heterozygosity (LOH) on mouse chromosomes 9 and 16, at regions syntenic with regions 3q, 3p21, 6q12, 15q24 and 22q of the human genome.


METHODS
Loss of heterozygosity in human islet cell tumours was analysed in a PCR based approach at regions of the human genome syntenic with the mouse loci linked to pancreatic betacell tumours as well as the MEN1 gene on chromosome 11q13. These included 35 microsatellite markers in the human chromosomal regions 3q, 3p21, 6q12, 11q13, 15q24 and 22q.


METHODS
21 patients diagnosed with insulinoma were analysed. Histologically, 16 tumours were benign, while 5 were malignant insulinomas.


RESULTS
Thirteen of 21 (62%) tumours were found to have loss of genetic material on chromosome 3. The shortest region of overlap implicated a deletion at 3p14.2-3p21 region, corresponding to the marker D3S1295. We did not detect a substantial frequency of LOH in the other syntenic regions, except for the region of MEN 1 gene on 11q13 found to be deleted in 6 (29%) cases, including 3 of 4 tumours from MEN 1 families. Deletions of 3p14. 2-3p21 were observed in 8 of 15 (53%) benign tumours, and in 5 of 6 (83%) malignant neoplasms.


CONCLUSIONS
These results indicate the high frequency of 3p14.2-3p21 deletions in human pancreatic betacell neoplasms. These finding suggest the presence of a tumour suppressor gene in this region, that may be important in the microevolution of these tumours towards malignancy.
Nikiforova
M N
MN
Division of Endocrinology/Metabolism, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0547, USA.
Nikiforov
Y E
YE
Biddinger
P
P
Gnepp
D R
DR
Grosembacher
L A
LA
Wajchenberg
B L
BL
Fagin
J A
JA
Cohen
R M
RM
D000328:Adult; D002880:Chromosomes, Human, Pair 11; D002884:Chromosomes, Human, Pair 15; D002892:Chromosomes, Human, Pair 22; D002893:Chromosomes, Human, Pair 3; D002896:Chromosomes, Human, Pair 6; D005260:Female; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D005819:Genetic Markers; D006801:Humans; D007340:Insulinoma / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction
D005819:Genetic Markers