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MGMT expression and pituitary tumours: relationship to tumour biology

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Abstract

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.

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References

  1. Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A (2006) High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 91(12):4769–4775

    Article  PubMed  CAS  Google Scholar 

  2. Fernandez A, Karavitaki N, Wass JA (2010) Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 72(3):377–382. doi:10.1111/j.1365-2265.2009.03667.x

    Article  Google Scholar 

  3. Melmed S (2011) Pathogenesis of pituitary tumors. Nat Rev Endocrinol 7(5):257–266. doi:10.1038/nrendo.2011.40

    Article  PubMed  CAS  Google Scholar 

  4. Pernicone PJ, Scheithauer BW, Sebo TJ, Kovacs KT, Horvath E, Young WF Jr, Lloyd RV, Davis DH, Guthrie BL, Schoene WC (1997) Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79(4):804–812

    Article  PubMed  CAS  Google Scholar 

  5. Chesnokova V, Zonis S, Kovacs K, Ben-Shlomo A, Wawrowsky K, Bannykh S, Melmed S (2008) p21(Cip1) restrains pituitary tumor growth. Proc Natl Acad Sci USA 105(45):17498–17503

    Article  PubMed  CAS  Google Scholar 

  6. Chesnokova V, Melmed S (2010) Pituitary senescence: the evolving role of Pttg. Mol Cell Endocrinol 326(1–2):55–59. doi:10.1016/j.mce.2010.02.012

    Article  PubMed  CAS  Google Scholar 

  7. Vandeva S, Tichomirowa MA, Zacharieva S, Daly AF, Beckers A (2010) Genetic factors in the development of pituitary adenomas. Endocr Dev 17:121–133. doi:10.1159/000262534

    Article  PubMed  CAS  Google Scholar 

  8. Gueorguiev M, Grossman AB (2009) Pituitary gland and beta-catenin signaling: from ontogeny to oncogenesis. Pituitary 12(3):245–255. doi:10.1007/s11102-008-0147-x

    Article  PubMed  CAS  Google Scholar 

  9. Dworakowska D, Grossman AB (2009) The pathophysiology of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 23(5):525–541

    Article  PubMed  CAS  Google Scholar 

  10. Asa SL, Ezzat S (2009) The pathogenesis of pituitary tumors. Annu Rev Pathol 4:97–126

    Article  PubMed  CAS  Google Scholar 

  11. Vidal S, Kovacs K, Horvath E, Rotondo F, Kuroki T, Lloyd RV, Scheithauer BW (2002) Topoisomerase IIalpha expression in pituitary adenomas and carcinomas: relationship to tumor behavior. Mod Pathol 15(11):1205–1212

    Article  PubMed  Google Scholar 

  12. Pan LX, Chen ZP, Liu YS, Zhao JH (2005) Magnetic resonance imaging and biological markers in pituitary adenomas with invasion of the cavernous sinus space. J Neurooncol 74(1):71–76

    Article  PubMed  Google Scholar 

  13. Qian ZR, Li CC, Yamasaki H, Mizusawa N, Yoshimoto K, Yamada S, Tashiro T, Horiguchi H, Wakatsuki S, Hirokawa M, Sano T (2002) Role of E-cadherin, alpha-, beta-, and gamma-catenins, and p120 (cell adhesion molecules) in prolactinoma behavior. Mod Pathol 15(12):1357–1365

    Article  PubMed  Google Scholar 

  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):536–543

    Article  Google 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):141–150

    Article  CAS  Google Scholar 

  16. Fadul CE, Kominsky AL, Meyer LP, Kingman LS, Kinlaw WB, Rhodes CH, Eskey CJ, Simmons NE (2006) Long-term response of pituitary carcinoma to temozolomide, Report of two cases. J Neurosurg 105(4):621–626

    Article  PubMed  Google Scholar 

  17. Neff LM, Weil M, Cole A, Hedges TR, Shucart W, Lawrence D, Zhu JJ, Tischler AS, Lechan RM (2007) Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists. Pituitary 10(1):81–86

    Article  PubMed  Google Scholar 

  18. Syro LV, Uribe H, Penagos LC, Ortiz LD, Fadul CE, Horvath E, Kovacs K (2006) Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm. Clin Endocrinol (Oxf) 65(4):552–553

    Article  Google Scholar 

  19. Moyes VJ, Alusi G, Sabin HI, Evanson J, Berney DM, Kovacs K, Monson JP, Plowman PN, Drake WM (2009) Treatment of Nelson’s syndrome with temozolomide. Eur J Endocrinol 160(1):115–119

    Article  PubMed  CAS  Google 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):226–233

    Article  CAS  Google 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 

  25. McCormack AI, Wass JA, Grossman AB (2011) Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status. Eur J Clin Invest 41(10):1133–1148. doi:10.1111/j.1365-2362.2011.02520.x

    Article  PubMed  CAS  Google Scholar 

  26. Lau Q, Scheithauer B, Kovacs K, Horvath E, Syro LV, Lloyd R (2010) MGMT immunoexpression in aggressive pituitary adenoma and carcinoma. Pituitary 13(4):367–379. doi:10.1007/s11102-010-0249-0

    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):1070–1080

    Article  PubMed  CAS  Google 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):553–559

    Google Scholar 

  29. Salehi F, Scheithauer BW, Kros JM, Lau Q, Fealey M, Erickson D, Kovacs K, Horvath E, Lloyd RV (2011) MGMT promoter methylation and immunoexpression in aggressive pituitary adenomas and carcinomas. J Neurooncol 104(3):647–657. doi:10.1007/s11060-011-0532-6

    Google 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

    Article  PubMed  Google Scholar 

  31. Lloyd RV, Kovacs K, Young WF (2004) Pituitary tumors. WHO classification of tumours of the endocrine organs. IARC Press, Lyon

  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

    Article  PubMed  CAS  Google 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

    Article  PubMed  CAS  Google Scholar 

  34. Liu L, Yang M, Kang R, Wang Z, Zhao Y, Yu Y, Xie M, Yin X, Livesey KM, Loze MT, Tang D, Cao L (2011) DAMP-mediated autophagy contributes to drug resistance. Autophagy 7(1):112–114

    Article  PubMed  Google 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

    Article  PubMed  CAS  Google Scholar 

  36. Srougi MC, Burridge K (2011) The nuclear guanine nucleotide exchange factors Ect2 and Net1 regulate RhoB-mediated cell death after DNA damage. PLoS One 6(2):e17108. doi:10.1371/journal.pone.0017108

    Article  PubMed  CAS  Google Scholar 

  37. Warmerdam DO, Kanaar R (2010) Dealing with DNA damage: relationships between checkpoint and repair pathways. Mutat Res 704(1–3):2–11. doi:10.1016/j.mrrev.2009.12.001

    PubMed  CAS  Google Scholar 

  38. Im JS, Jung BH, Kim SE, Lee KH, Lee JK (2010) Per3, a circadian gene, is required for Chk2 activation in human cells. FEBS Lett 584(23):4731–4734. doi:10.1016/j.febslet.2010.11.003

    Article  PubMed  CAS  Google Scholar 

  39. Kaina B (2003) DNA damage-triggered apoptosis: critical role of DNA repair, double-strand breaks, cell proliferation and signaling. Biochem Pharmacol 66(8):1547–1554. doi:S0006295203005100

    Google Scholar 

  40. Egly JM, Coin F (2011) A history of TFIIH: two decades of molecular biology on a pivotal transcription/repair factor. DNA Repair (Amst). doi:10.1016/j.dnarep.2011.04.021

    Google Scholar 

  41. Cordin O, Banroques J, Tanner NK, Linder P (2006) The DEAD-box protein family of RNA helicases. Gene 367:17–37. doi:10.1016/j.gene.2005.10.019

    Article  PubMed  CAS  Google Scholar 

  42. Kohler A, Hurt E (2010) Gene regulation by nucleoporins and links to cancer. Mol Cell 38(1):6–15. doi:10.1016/j.molcel.2010.01.040

    Article  PubMed  Google Scholar 

  43. Pereira LA, Klejman MP, Timmers HT (2003) Roles for BTAF1 and Mot1p in dynamics of TATA-binding protein and regulation of RNA polymerase II transcription. Gene 315:1–13. doi:S0378111903007145

    Google Scholar 

  44. Yu Y, Feng YM (2010) The role of kinesin family proteins in tumorigenesis and progression: potential biomarkers and molecular targets for cancer therapy. Cancer 116(22):5150–5160. doi:10.1002/cncr.25461

    Article  PubMed  CAS  Google Scholar 

  45. Fumoto K, Hoogenraad CC, Kikuchi A (2006) GSK-3beta-regulated interaction of BICD with dynein is involved in microtubule anchorage at centrosome. EMBO J 25(24):5670–5682. doi:10.1038/sj.emboj.7601459

    Article  PubMed  CAS  Google Scholar 

  46. Salehi F, Scheithauer BW, Moyes VJ, Drake WM, Syro LV, Manoranjan B, Sharma S, Horvath E, Kovacs K (2010) Low Immunohistochemical Expression of MGMT in ACTH Secreting Pituitary Tumors of Patients with Nelson Syndrome. Endocr Pathol 21(4):227–229. doi:10.1007/s12022-010-9138-3

    Google Scholar 

  47. Mineura K, Watanabe K, Yanagisawa T, Kowada M (1996) Quantification of O6-methylguanine-DNA methyltransferase mRNA in human brain tumors. Biochim Biophys Acta 1289(1):105–109

    Article  PubMed  Google Scholar 

  48. Citron M, Graver M, Schoenhaus M, Chen S, Decker R, Kleynerman L, Kahn LB, White A, Fornace AJ Jr, Yarosh D (1992) Detection of messenger RNA from O6-methylguanine-DNA methyltransferase gene MGMT in human normal and tumor tissues. J Natl Cancer Inst 84(5):337–340

    Article  PubMed  CAS  Google Scholar 

  49. Fornace AJ Jr, Papathanasiou MA, Hollander MC, Yarosh DB (1990) Expression of the O6-methylguanine-DNA methyltransferase gene MGMT in MER + and MER- human tumor cells. Cancer Res 50(24):7908–7911

    PubMed  CAS  Google Scholar 

  50. Boldogh I, Ramana CV, Chen Z, Biswas T, Hazra TK, Grosch S, Grombacher T, Mitra S, Kaina B (1998) Regulation of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling. Cancer Res 58(17):3950–3956

    PubMed  CAS  Google Scholar 

  51. Ozanne BW, McGarry L, Spence HJ, Johnston I, Winnie J, Meagher L, Stapleton G (2000) Transcriptional regulation of cell invasion: AP-1 regulation of a multigenic invasion programme. Eur J Cancer 36(13 Spec No):1640–1648. doi:S0959-8049(00)00175-1

    Google 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):2807–2815

    Article  PubMed  CAS  Google Scholar 

  53. Golding SE, Morgan RN, Adams BR, Hawkins AJ, Povirk LF, Valerie K (2009) Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells. Cancer Biol Ther 8(8):730–738

    Article  PubMed  CAS  Google Scholar 

  54. Lavon I, Fuchs D, Zrihan D, Efroni G, Zelikovitch B, Fellig Y, Siegal T (2007) Novel mechanism whereby nuclear factor kappaB mediates DNA damage repair through regulation of O(6)-methylguanine-DNA-methyltransferase. Cancer Res 67(18):8952–8959

    Article  PubMed  CAS  Google Scholar 

  55. Shimura T, Kakuda S, Ochiai Y, Nakagawa H, Kuwahara Y, Takai Y, Kobayashi J, Komatsu K, Fukumoto M (2010) Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3beta-mediated cyclin D1 overexpression. Oncogene 29(34):4826–4837. doi:10.1038/onc.2010.238

    Article  PubMed  CAS  Google Scholar 

  56. Niture SK, Doneanu CE, Velu CS, Bailey NI, Srivenugopal KS (2005) Proteomic analysis of human O6-methylguanine-DNA methyltransferase by affinity chromatography and tandem mass spectrometry. Biochem Biophys Res Commun 337(4):1176–1184. doi:10.1016/j.bbrc.2005.09.177

    Article  PubMed  CAS  Google Scholar 

  57. Nouspikel T (2009) DNA repair in mammalian cells : nucleotide excision repair: variations on versatility. Cell Mol Life Sci 66(6):994–1009. doi:10.1007/s00018-009-8737-y

    Article  PubMed  CAS  Google Scholar 

  58. Gommans WM, Haisma HJ, Rots MG (2005) Engineering zinc finger protein transcription factors: the therapeutic relevance of switching endogenous gene expression on or off at command. J Mol Biol 354(3):507–519. doi:10.1016/j.jmb.2005.06.082

    Article  PubMed  CAS  Google Scholar 

  59. Witkiewicz-Kucharczyk A, Bal W (2006) Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis. Toxicol Lett 162(1):29–42. doi:10.1016/j.toxlet.2005.10.018

    Article  PubMed  CAS  Google 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

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Cancer Genetics Unit, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia

    Ann McCormack & Roderick Clifton-Bligh

  2. Department of Endocrinology, St Vincent’s Hospital and Garvan Institute of Medical Research, Sydney, NSW, Australia

    Ann McCormack

  3. Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia

    Warren Kaplan

  4. Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia

    Anthony J. Gill

  5. Department of Anatomical Pathology, University of Sydney, Sydney, Australia

    Anthony J. Gill

  6. Department of Neurosurgery, Royal North Shore and North Shore Private Hospitals, Sydney, NSW, Australia

    Nicholas Little & Raymond Cook

  7. Faculty of Medicine, University of Sydney, Sydney, Australia

    Bruce Robinson

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  1. Ann McCormack
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Correspondence to Ann McCormack.

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McCormack, A., Kaplan, W., Gill, A.J. et al. MGMT expression and pituitary tumours: relationship to tumour biology. Pituitary 16, 208–219 (2013). https://doi.org/10.1007/s11102-012-0406-8

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