PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jmedgeneJournal of Medical GeneticsVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
 
J Med Genet. 2000 June; 37(6): 410–414.
PMCID: PMC1734615

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

Abstract

PPARγ, the gamma isoform of a family of peroxisome proliferator activated receptors, plays a key role in adipocyte differentiation. Recently, its broad expression in multiple tissues and several epithelial cancers has been shown. Further, somatic loss of function mutations in PPARγ have been found in primary colorectal carcinomas. We sought to determine if somatic high penetrance mutations in this gene might also play a role in glioblastoma multiforme (GBM). We also examined this gene to determine if common low penetrance polymorphic alleles might lend low level susceptibility to GBM in the general population. No somatic high penetrance mutations were detected in 96 sporadic GBMs. However, polymorphic alleles at codons 12 and 449 were significantly over-represented among the 27 unrelated American patients 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 confirmed with a second validation set of American patients. When both American series were combined, polymorphic H449H was over-represented among cases versus 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 PPARγ polymorphisms may be acting in a low penetrance predisposing manner. However, these associations were not found in a German population, possibly arguing that if these variants are in linkage disequilibrium with a third locus, then this effect is relatively new, after the settlement of the American colonies.


Keywords: peroxisome proliferator activated receptors; sequence variants; tumour suppressor

Full Text

The Full Text of this article is available as a PDF (146K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994 Dec 30;79(7):1147–1156. [PubMed]
  • Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998 Apr;47(4):507–514. [PubMed]
  • Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell. 1995 Dec 1;83(5):813–819. [PubMed]
  • Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995 Dec 1;83(5):803–812. [PubMed]
  • Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, et al. Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med. 1998 Sep;4(9):1046–1052. [PubMed]
  • Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, Fletcher C, Singer S, Spiegelman BM. Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell. 1998 Feb;1(3):465–470. [PubMed]
  • Brockman JA, Gupta RA, Dubois RN. Activation of PPARgamma leads to inhibition of anchorage-independent growth of human colorectal cancer cells. Gastroenterology. 1998 Nov;115(5):1049–1055. [PubMed]
  • DuBois RN, Gupta R, Brockman J, Reddy BS, Krakow SL, Lazar MA. The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers. Carcinogenesis. 1998 Jan;19(1):49–53. [PubMed]
  • Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerx J. Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med. 1998 Sep;4(9):1053–1057. [PubMed]
  • Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA, Evans RM. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med. 1998 Sep;4(9):1058–1061. [PubMed]
  • Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, de la Chapelle A, Spiegelman BM, Eng C. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell. 1999 Jun;3(6):799–804. [PubMed]
  • Cullingford TE, Bhakoo K, Peuchen S, Dolphin CT, Patel R, Clark JB. Distribution of mRNAs encoding the peroxisome proliferator-activated receptor alpha, beta, and gamma and the retinoid X receptor alpha, beta, and gamma in rat central nervous system. J Neurochem. 1998 Apr;70(4):1366–1375. [PubMed]
  • Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz M d, Moller DE, Berger J. Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2. Biochem Biophys Res Commun. 1996 Jul 16;224(2):431–437. [PubMed]
  • Inskip PD, Linet MS, Heineman EF. Etiology of brain tumors in adults. Epidemiol Rev. 1995;17(2):382–414. [PubMed]
  • Mathew CG, Smith BA, Thorpe K, Wong Z, Royle NJ, Jeffreys AJ, Ponder BA. Deletion of genes on chromosome 1 in endocrine neoplasia. Nature. 1987 Aug 6;328(6130):524–526. [PubMed]
  • Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR. Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun. 1997 Dec 18;241(2):270–274. [PubMed]
  • Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May;16(1):64–67. [PubMed]
  • Dahia PL, Aguiar RC, Alberta J, Kum JB, Caron S, Sill H, Marsh DJ, Ritz J, Freedman A, Stiles C, et al. PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies. Hum Mol Genet. 1999 Feb;8(2):185–193. [PubMed]
  • Gimm O, Neuberg DS, Marsh DJ, Dahia PL, Hoang-Vu C, Raue F, Hinze R, Dralle H, Eng C. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene. 1999 Feb 11;18(6):1369–1373. [PubMed]
  • Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Lebel P, Dallongeville J, Deeb S, Auwerx J, Amouyel P. A genetic polymorphism of the peroxisome proliferator-activated receptor gamma gene influences plasma leptin levels in obese humans. Hum Mol Genet. 1998 Mar;7(3):435–440. [PubMed]
  • de la Chapelle A, Wright FA. Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12416–12423. [PubMed]
  • Deeb SS, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998 Nov;20(3):284–287. [PubMed]
  • Kaplan S, Novikov I, Modan B. Nutritional factors in the etiology of brain tumors: potential role of nitrosamines, fat, and cholesterol. Am J Epidemiol. 1997 Nov 15;146(10):832–841. [PubMed]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group