MGMT expression and pituitary tumours: relationship to tumour biology
- 433 Downloads
Over the past half decade, temozolomide, an oral akylating chemotherapeutic agent, has been shown to have significant activity in the management of aggressive pituitary tumours. The expression of 06-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is an important predictor of response to therapy. Low MGMT expression has been reported with a higher frequency amongst more aggressive pituitary tumours, suggesting MGMT may play a role in pituitary tumour progression. In this study, we performed a microarray analysis to determine whether there was a distinct gene expression profile between tumours with low MGMT and high MGMT expression. Overall, 1,403 differentially expressed genes were identified with raw p values less than 0.05. Gene set enrichment analysis (GSEA) revealed significant differences in the gene expression profile between high and low MGMT expressing pituitary tumours. High MGMT expressing pituitary tumours were found to have upregulation of components of the FGFR family and downstream signaling cascades such as PI3 K/Akt and MAPK pathways. Activation of genes involved in the DNA damage response and DNA repair pathways, as well as genes involved in transcription, were identified in pituitary tumours with low MGMT expression. These results form the basis of our proposed model to describe the role of MGMT in pituitary tumorigenesis.
KeywordsPituitary tumour Temozolomide MGMT Pituitary tumorigenesis
This work was supported by an NHMRC Medical Postgraduate Scholarship and a Cancer Institute of NSW Research Scholar Award. We thank Adele Clarkson, Department of Anatomical Pathology, Royal North Shore Hospital for assistance with the immunohistochemistry.
Conflict of interest
The authors declare that they have no conflict of interest.
- 14.Filippella M, Galland F, Kujas M, Young J, Faggiano A, Lombardi G, Colao A, Meduri G, Chanson P (2006) Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin Endocrinol (Oxf) 65(4):536–543CrossRefGoogle Scholar
- 15.McCabe CJ, Khaira JS, Boelaert K, Heaney AP, Tannahill LA, Hussain S, Mitchell R, Olliff J, Sheppard MC, Franklyn JA, Gittoes NJ (2003) Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour. Clin Endocrinol (Oxf) 58(2):141–150CrossRefGoogle Scholar
- 20.Mohammed S, Kovacs K, Mason W, Smyth H, Cusimano MD (2009) Use of temozolomide in aggressive pituitary tumors: case report. Neurosurgery 64(4):E773–E774 (discussion E774)Google Scholar
- 21.McCormack AI, McDonald KL, Gill AJ, Clark SJ, Burt MG, Campbell KA, Braund WJ, Little NS, Cook RJ, Grossman AB, Robinson BG, Clifton-Bligh RJ (2009) Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol (Oxf) 71(2):226–233CrossRefGoogle Scholar
- 22.Raverot G, Sturm N, de Fraipont F, Muller M, Salenave S, Caron P, Chabre O, Chanson P, Cortet-Rudelli C, Assaker R, Dufour H, Gaillard S, Francois P, Jouanneau E, Passagia JG, Bernier M, Cornelius A, Figarella-Branger D, Trouillas J, Borson-Chazot F, Brue T (2010) Temozolomide Treatment in Aggressive Pituitary Tumors and Pituitary Carcinomas: a French Multicenter Experience. J Clin Endocrinol Metab 95(10):4592–4599. doi: 10.1210/jc.2010-0644 Google Scholar
- 23.Bush ZM, Longtine JA, Cunningham T, Schiff D, Jane JA Jr, Vance ML, Thorner MO, Laws ER Jr, Lopes MB (2010) Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O6-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab 95(11):E280–E290. doi: 10.1210/jc.2010-0441 Google Scholar
- 24.Losa M, Mazza E, Terreni MR, McCormack A, Gill AJ, Motta M, Cangi MG, Talarico A, Mortini P, Reni M (2010) Salvage therapy with Temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases. Eur J Endocrinol 163(6):843-851. doi: 10.1530/EJE-10-0629 Google Scholar
- 27.Widhalm G, Wolfsberger S, Preusser M, Woehrer A, Kotter MR, Czech T, Marosi C, Knosp E (2009) O(6)-methylguanine DNA methyltransferase immunoexpression in nonfunctioning pituitary adenomas: are progressive tumors potential candidates for temozolomide treatment? Cancer 115(5):1070–1080PubMedCrossRefGoogle Scholar
- 28.Takeshita A, Inoshita N, Taguchi M, Okuda C, Fukuhara N, Oyama K, Ohashi K, Sano T, Takeuchi Y, Yamada S (2009) High incidence of low O6-methylguanine DNA methyltransferase (MGMT) expression in invasive macroadenomas of Cushing’s disease. Eur J Endocrinol 161(4):553–559Google Scholar
- 30.Salehi F, Scheithauer BW, Kovacs K, Horvath E, Syro LV, Sharma S, Manoranjan B, Cusimano M (2012) O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemical expression in pituitary corticotroph adenomas. Neurosurgery 70(2):491–496. doi: 10.1227/NEU.0b013e318230ac63 PubMedCrossRefGoogle Scholar
- 31.Lloyd RV, Kovacs K, Young WF (2004) Pituitary tumors. WHO classification of tumours of the endocrine organs. IARC Press, LyonGoogle Scholar
- 32.Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550. doi: 10.1073/pnas.0506580102 PubMedCrossRefGoogle Scholar
- 33.Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267–273. doi: 10.1038/ng1180 PubMedCrossRefGoogle Scholar
- 35.Mlynarczuk-Bialy I, Roeckmann H, Kuckelkorn U, Schmidt B, Umbreen S, Golab J, Ludwig A, Montag C, Wiebusch L, Hagemeier C, Schadendorf D, Kloetzel PM, Seifert U (2006) Combined effect of proteasome and calpain inhibition on cisplatin-resistant human melanoma cells. Cancer Res 66(15):7598–7605. doi: 10.1158/0008-5472.CAN-05-2614 PubMedCrossRefGoogle Scholar
- 52.Fontijn D, Adema AD, Bhakat KK, Pinedo HM, Peters GJ, Boven E (2007) O6-methylguanine-DNA-methyltransferase promoter demethylation is involved in basic fibroblast growth factor induced resistance against temozolomide in human melanoma cells. Mol Cancer Ther 6(10):2807–2815PubMedCrossRefGoogle Scholar
- 60.Chahal M, Xu Y, Lesniak D, Graham K, Famulski K, Christensen JG, Aghi M, Jacques A, Murray D, Sabri S, Abdulkarim B (2010) MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib. Neuro Oncol 12(8):822–833. doi: 10.1093/neuonc/noq017 PubMedCrossRefGoogle Scholar