Over-representation of PPAR gamma sequence variants in sporadic cases of glioblastoma multiforme: preliminary evidence for common low penetrance modifiers for brain tumour risk in the general population

PPAR gamma, the gamma isoform of a family of peroxisome proliferator activa ted receptors, plays a key role in adipocyte differentiation. Recently, its broad expression in multiple tissues and several epithelial cancers has be en shown. Further, somatic loss of function mutations in PPAR gamma have be en found in primary colorectal carcinomas. We sought to determine if somati c high penetrance mutations in this gene might also play a role in glioblas toma multiforme (GBM). We also examined this gene to determine if common lo w penetrance polymorphic alleles might lend low level susceptibility to GEM in the general population. No somatic high penetrance mutations were detec ted in 96 sporadic GBMs. However, polymorphic alleles at codons 12 and 449 were significantly over-represented among the 27 unrelated American patient s with sporadic GBM compared to 80 race matched controls. While nine (33%) were heterozygous for the P12A variant, c.34C/G (cytosine to guanine change at nucleotide 34), 12 (15%) controls were heterozygous for P12A (p<0.05). Similarly, 13 of 26 (50%) glioblastoma patients compared to 10 of 80 (12%) normal controls were found to have the heterozygous H449H polymorphism (p<0 .001). The over-representation of H449H in glioblastoma patients was confir med with a second validation set of American patients. When both American s eries were combined, polymorphic H449H was over-represented among cases ver sus controls (p<0.001) and there was a similar trend (p=0.07) for P12A. The precise mechanism for this association is unknown but these PPAR gamma pol ymorphisms may be acting ill a low penetrance predisposing manner. However, these associations were not found in a German population, possibly arguing that if variants are in linkage disequilibrium with a third locus, then th is effect is relatively new, after the settlement of the American colonies.