Somatic mutations in glioblastoma are associated with methylguanine-DNA methyltransferase methylation

McDonald,Kerrie  L.; Tabone,Tania; Nowak,Anna  K.; Erber,Wendy  N.

doi:10.3892/ol.2015.2980

Somatic mutations in glioblastoma are associated with methylguanine-DNA methyltransferase methylation

Authors:
- Kerrie L. McDonald
- Tania Tabone
- Anna K. Nowak
- Wendy N. Erber
View Affiliations

Affiliations: Cure Brain Cancer Neuro‑oncology Group, Prince of Wales Clinical School, Lowy Cancer Research Centre C25, University of New South Wales, Sydney, NSW 2052, Australia, School of Pathology and Laboratory Medicine, University of Western Australia, Crawley WA 6009, Australia, Harry Perkins Institute of Medical Research, Nedlands WA 6009, Australia
Published online on: February 20, 2015 https://doi.org/10.3892/ol.2015.2980
Pages: 2063-2067
Copyright: © McDonald et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The high level of methylguanine‑DNA methyltransferase (MGMT) in glioblastoma is responsible for resistance to alkylating agents, such as temozolomide (TMZ). In glioblastomas with a methylated MGMT promoter, MGMT deficiency is presumed, resulting in an enhanced effect of TMZ. The aim of the present study was to investigate whether genomic alterations work synergistically with MGMT methylation status and contribute to the response to treatment and overall prognosis in glioblastoma. The current study included a cohort of 35 glioblastoma patients, with MGMT promoter methylation present in 48% of tumors. MGMT methylation was associated with significantly longer median survival (29.0 months) compared with patients without MGMT methylated tumors (12.0 months), as well as longer median time to progression following TMZ treatment (13.2 months, compared with 5.6 months for patients with an unmethylated MGMT status). In addition, somatic variants in hot spot exonic regions of 50 key cancer genes were examined in these glioblastomas. Non‑synonymous mutations in methylated MGMT glioblastomas were four times higher compared with unmethylated MGMT glioblastomas. Furthermore, significantly increased frequencies of mutations in the TP53, CDKN2A, PTEN and PIK3CA genes were detected in MGMT methylated glioblastomas. The relative significance of these mutations, and their contribution to TMZ sensitivity, adjunct to MGMT methylation, require further investigation in a larger cohort.

View Figures

View References

1	Stupp R, Mason WP, van den Bent MJ, et al: European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
2	Burnet NG, Jefferies SJ, Benson RJ, et al: Years of life lost (YLL) from cancer is an important measure of population burden – and should be considered when allocating research funds. Br J Cancer. 92:241–245. 2005.PubMed/NCBI
3	Leibetseder A, Ackerl M, Flechl B, et al: Outcome and molecular characteristics of adolescent and young adult patients with newly diagnosed primary glioblastoma: a study of the Society of Austrian Neurooncology (SANO). Neuro Oncol. 15:112–121. 2013. View Article : Google Scholar : PubMed/NCBI
4	Kinsella TJ, Collins J, Rowland J, et al: Pharmacology and phase I/II study of continuous intravenous infusions of iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma multiforme. J Clin Oncol. 6:871–879. 1988.PubMed/NCBI
5	Hammoud MA, Sawaya R, Shi W, Thall PF and Leeds NE: Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J Neurooncol. 27:65–73. 1996. View Article : Google Scholar : PubMed/NCBI
6	Gulati S, Jakola AS, Nerland US, Weber C and Solheim O: The risk of getting worse: surgically acquired deficits, perioperative complications, and functional outcomes after primary resection of glioblastoma. World Neurosurg. 76:572–579. 2011. View Article : Google Scholar : PubMed/NCBI
7	Friedman HS, Kerby T and Calvert H: Temozolomide and treatment of malignant glioma. Clin Cancer Res. 6:2585–2597. 2000.PubMed/NCBI
8	Roos WP and Kaina B: DNA damage-induced apoptosis: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 332:237–248. 2013. View Article : Google Scholar : PubMed/NCBI
9	Esteller M, Hamilton SR, Burger PC, et al: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 59:793–797. 1999.PubMed/NCBI
10	Felsberg J, Thon N, Eigenbrod S, et al: German Glioma Network: Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer. 129:659–670. 2011. View Article : Google Scholar : PubMed/NCBI
11	Esteller M: Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur J Cancer. 36:2294–2300. 2000. View Article : Google Scholar : PubMed/NCBI
12	Esteller M: CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 21:5427–5440. 2002. View Article : Google Scholar : PubMed/NCBI
13	Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 352:997–1003. 2005. View Article : Google Scholar : PubMed/NCBI
14	Reifenberger G, Hentschel B, Felsberg J, et al: German Glioma Network: Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int J Cancer. 131:1342–1350. 2012. View Article : Google Scholar : PubMed/NCBI
15	Stummer W, Nestler U, Stockhammer F, et al: Favorable outcome in the elderly cohort treated by concomitant temozolomide radiochemotherapy in a multicentric phase II safety study of 5-ALA. J Neurooncol. 103:361–370. 2011. View Article : Google Scholar : PubMed/NCBI
16	Cancer Genome Atlas Research Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 455:1061–1068. 2008. View Article : Google Scholar : PubMed/NCBI
17	Verhaak RG, Hoadley KA, Purdom E, et al: Cancer Genome Atlas Research Network: Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 17:98–110. 2010. View Article : Google Scholar : PubMed/NCBI
18	Brennan CW, Verhaak RG, McKenna A, et al: TCGA Research Network: The somatic genomic landscape of glioblastoma. Cell. 155:462–477. 2013. View Article : Google Scholar : PubMed/NCBI
19	McDonald KL, Rapkins RW, Olivier J, et al: The T genotype of the MGMT C>T (rs16906252) enhancer single-nucleotide polymorphism (SNP) is associated with promoter methylation and longer survival in glioblastoma patients. Eur J Cancer. 49:360–368. 2013. View Article : Google Scholar : PubMed/NCBI
20	Jeuken J, Sijben A, Alenda C, et al: Robust detection of EGFR copy number changes and EGFR variant III: technical aspects and relevance for glioma diagnostics. Brain Pathol. 19:661–671. 2009. View Article : Google Scholar : PubMed/NCBI
21	Tabone T, Abuhusain HJ, Nowak AK, et al: Multigene profiling to identify alternative treatment options for glioblastoma: a pilot study. J Clin Pathol. 67:550–555. 2014. View Article : Google Scholar : PubMed/NCBI
22	Esteller M, Garcia-Foncillas J, Andion E, et al: Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 343:1350–1354. 2000. View Article : Google Scholar : PubMed/NCBI
23	Hegi ME, Diserens AC, Godard S, et al: Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res. 10:1871–1874. 2004. View Article : Google Scholar : PubMed/NCBI
24	Pegg AE: Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res. 50:6119–6129. 1990.PubMed/NCBI
25	Christians A, Hartmann C, Benner A, et al: Prognostic value of three different methods of MGMT promoter methylation analysis in a prospective trial on newly diagnosed glioblastoma. PloS one. 7:e334492012. View Article : Google Scholar : PubMed/NCBI
26	Karayan-Tapon L, Quillien V, Guilhot J, et al: Prognostic value of O6-methylguanine-DNA methyltransferase status in glioblastoma patients, assessed by five different methods. J Neurooncol. 97:311–322. 2010. View Article : Google Scholar : PubMed/NCBI
27	Rosty C, Young JP, Walsh MD, et al: PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival. PLoS One. 8:e654792013. View Article : Google Scholar : PubMed/NCBI
28	Shen L, Kondo Y, Rosner GL, et al: MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst. 97:1330–1338. 2005. View Article : Google Scholar : PubMed/NCBI