O6-methylguanine-DNA methyltransferase (MGMT) Promoter methylation is a rare event in soft tissue sarcoma

Radiation Oncology

Peter Hohenberger³  Frederik Wenz¹  Philipp Ströbel²  Christian Sauer²  Maren Hille³  Jens Jakob³ 

[1] Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, Th.-Kutzer-Ufer 1-3, Mannheim 68137, Germany;Department of Pathology, University Medical Center Mannheim, University of Heidelberg, Th.-Kutzer-Ufer 1-3, Mannheim, 68137, Germany;Division of Surgical Oncology & Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Th.-Kutzer-Ufer 1-3, Mannheim, 68137, Germany

关键词: Radiation therapy;    Epigenetic gene silencing;    Temozolomide;    Promoter methylation;    O6-methylguanine–DNA methyltransferase;    Soft tissue sarcoma;   

Others  :  1155136
DOI  :  10.1186/1748-717X-7-180

 received in 2012-09-11, accepted in 2012-10-07,  发布年份 2012

【 摘 要 】

Background

Gene silencing of O6-methylguanine–DNA methyltransferase (MGMT) by promoter methylation improves the outcome of glioblastoma patients after combined therapy of alkylating chemotherapeutic agents and radiation. The purpose of this study was to assess the frequency of MGMT promoter methylation in soft tissue sarcoma to identify patients eligible for alkylating agent chemotherapy such as temozolomide.

Findings

Paraffin tumor blocks of 75 patients with representative STS subtypes were evaluated. The methylation status of the MGMT promoter was assessed by methylation-specific polymerase-chain-reaction analysis (PCR). Furthermore, immunohistochemistry was applied to verify expression of MGMT. MGMT gene silencing was assumed if MGMT promoter methylation was present and the fraction of tumor cells expressing MGMT was 20% or less. Methylation specific PCR detected methylated MGMT promoter in 10/75 cases. Immunohistochemical staining of nuclear MGMT was negative in 15/75 cases. 6/75 tumor samples showed MGMT promoter methylation and negative immunohistochemical nuclear staining of MGMT. In none of the tested STS subtypes we found a fraction of tumors with MGMT silencing exceeding 22%.

Conclusion

MGMT gene silencing is a rare event in soft tissue sarcoma and cannot be recommended as a selection criterion for the therapy of STS patients with alkylating agents such as temozolomide.

【 授权许可】

   
2012 Jakob et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Casali PG, Blay JY: Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010, 21(5):198-203.
• [2]Penel N, Van Glabbeke M, Marreaud S, Ouali M, Blay JY, Hohenberger P: Testing new regimens in patients with advanced soft tissue sarcoma: analysis of publications from the last 10 years. Ann Oncol 2010, 22(6):1266-1272.
• [3]Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C: Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 1997, 23(1):35-61.
• [4]Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005, 352(10):987-996.
• [5]Hegi ME, Diserens AC, Gorlia T, Hamou MF, De Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al.: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005, 352(10):997-1003.
• [6]Garcia Del Muro X, Lopez-Pousa A, Martin J, Buesa JM, Martinez-Trufero J, Casado A, Poveda A, Cruz J, Bover I, Maurel J: A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer 2005, 104(8):1706-1712.
• [7]Woll PJ, Judson I, Lee SM, Rodenhuis S, Nielsen OS, Buesa JM, Lorigan PC, Leyvraz S, Hermans C, van Glabbeke M, et al.: Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 1999, 35(3):410-412.
• [8]Jakob J, Wenz F, Dinter DJ, Strobel P, Hohenberger P: Preoperative intensity-modulated radiotherapy combined with temozolomide for locally advanced soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 2009, 75(3):810-816.
• [9]Palmisano WA, Divine KK, Saccomanno G, Gilliland FD, Baylin SB, Herman JG, Belinsky SA: Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer research 2000, 60(21):5954-5958.
• [10]Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, et al.: Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 2009, 101(1):124-131.
• [11]Preusser M: MGMT analysis at DNA, RNA and protein levels in glioblastoma tissue. Histology and histopathology 2009, 24(4):511-518.
• [12]Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, Hegi ME: MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nature reviews Neurology 2010, 6(1):39-51.
• [13]Kim JI, Suh JT, Choi KU, Kang HJ, Shin DH, Lee IS, Moon TY, Kim WT: Inactivation of O6-methylguanine-DNA methyltransferase in soft tissue sarcomas: association with K-ras mutations. Hum Pathol 2009, 40(7):934-941.
• [14]Kawaguchi K, Oda Y, Saito T, Yamamoto H, Takahira T, Kobayashi C, Tamiya S, Tateishi N, Iwamoto Y, Tsuneyoshi M: DNA hypermethylation status of multiple genes in soft tissue sarcomas. Mod Pathol 2006, 19(1):106-114.
• [15]Scurr M: Histology-Driven Chemotherapy in Soft Tissue Sarcomas. Curr Treat Options Oncol 2011, 12(1):32-45.