Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors.
Our previous comparative genomic hybridization study on sporadic endocrine pancreatic tumors (EPTs) revealed frequent losses on chromosomes 11q, 3p, and 6q. The aim of this study was to evaluate the importance of 6q losses in the oncogenesis of sporadic EPTs and to narrow down the smallest regions of allelic deletion. A multimodal approach combining polymerase chain reaction-based allelotyping, double-target fluorescence in situ hybridization, and comparative genomic hybridization was used in a collection of 109 sporadic EPTs from 93 patients. Nine polymorphic microsatellite markers (6q13 to 6q25-q27) were investigated, demonstrating a loss of heterozygosity (LOH) in 62.2% of the patients. A LOH was significantly more common in tumors >2 cm in diameter than below this threshold as well as in malignant than in benign tumors. We were able to narrow down the smallest regions of allelic deletion at 6q22.1 (D6S262) and 6q23-q24 (D6S310-UTRN) with LOH-frequencies of 50.0% and 41.2 to 56.3%, respectively. Several promising tumor suppressor candidates are located in these regions. Additional fluorescence in situ hybridization analysis on 46 EPTs using three locus-specific probes (6q21, 6q22, and 6q27) as well as a centromere 6-specific probe revealed complete loss of chromosome 6 especially in metastatic disease. We conclude that the two hot spots found on 6q may harbor putative tumor suppressor genes involved not only in the oncogenesis but maybe also in the malignant and metastatic progression of sporadic EPTs.
Barghorn
A
A
Department of Pathology, University of Zürich, Zürich, Switzerland. University of Maastricht, Maastricht, The Netherlands. andre.barghorn@pty.usz.ch
Speel
E J
EJ
Farspour
B
B
Saremaslani
P
P
Schmid
S
S
Perren
A
A
Roth
J
J
Heitz
P U
PU
Komminoth
P
P
D007516:Adenoma, Islet Cell / Q000235:genetics / Q000473:pathology; D002896:Chromosomes, Human, Pair 6; D018450:Disease Progression; D005260:Female; D016147:Genes, Tumor Suppressor; D005935:Glucagonoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D003969:Vipoma / Q000235:genetics / Q000473:pathology