Mutational analysis of PPARG as a candidate tumour suppressor gene in enteropancreatic endocrine tumours.
OBJECTIVE
Loss of heterozygosity (LOH) or deletion of chromosome 3p is a frequent finding in enteropancreatic endocrine tumours (EPETs), suggesting the pathogenetic involvement of one or more tumour suppressor genes on 3p. PPARG, the gene encoding the gamma isoform of the peroxisome proliferator-activated receptor (PPARgamma), is highly expressed in normal human pancreatic islet cells, is located at 3p25, and has been reported to sustain loss-of-function mutations in human colorectal carcinomas. Additionally, the development of islet cell hyperplasia in an islet cell-specific pparg knockout mouse has further emphasized the attractiveness of PPARG as a candidate gene important in the pathogenesis of EPETs. Therefore, we sought to examine PPARG for intragenic inactivating mutations, the evidence needed to rigorously establish it as a tumour suppressor in EPETs.


METHODS
Twenty-three EPETs from 20 patients were examined for coding region mutations in PPARG and for LOH on 3p at microsatellite markers flanking PPARG.


RESULTS
LOH on 3p was detected in tumours from six patients (30%), but no intragenic mutations were detected in PPARG, whether or not LOH was present.


CONCLUSIONS
These findings strongly suggest that PPARG does not commonly function as a classical tumour suppressor gene in the pathogenesis of EPETs.
Costa-Guda
Jessica
J
Center for Molecular Medicine and Division of Endocrinology and Metabolism, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
Rosen
Evan D
ED
Jensen
Robert T
RT
Chung
Daniel C
DC
Arnold
Andrew
A
D004252:DNA Mutational Analysis; D004701:Endocrine Gland Neoplasms / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D047495:PPAR gamma / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*
D047495:PPAR gamma