The T genotype of the MGMT C&gt;T (rs16906252) enhancer single-nucleotide polymorphism (SNP) is associated with promoter methylation and longer survival in glioblastoma patients

McDonald, Kerrie L.; Rapkins, Robert W.; Olivier, Jake; Zhao, Liang; Nozue, Kyoko; Lu, Dongfang; Tiwari, S.; Kuroiwa-Trzmielina, Joice; Brewer, Janice; Wheeler, Helen; Hitchins, Megan P.

doi:10.1016/j.ejca.2012.08.012

Cited by 55 publications

(65 citation statements)

References 22 publications

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“…We and others have previously reported on the functional effects of several SNPs in the MGMT P/E region [14,21]. While only a few investigators have assessed the effect of some of these SNPs on cancer risk, putative associations with MGMT promoter methylation as well as chemotherapeutic responses, these studies have yielded conflicting results [17][18][19][20][21][24][25][26][27][28][29][30][31][32][33]. This controversy is not surprising because SNPs are not arrayed independently in the genome, but rather occur as combinations forming well-defined haplotypes [34].…”

Section: Introductionmentioning

confidence: 95%

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MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression

Cross

Speidel

et al. 2016

Cell Oncol.

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Section: Introductionmentioning

confidence: 95%

“…Both CpG methylation [15,16] and single-nucleotide polymorphisms (SNPs) in the MGMT promoter/enhancer (P/E) region have been found to play important roles in the regulation of MGMT transcription [17][18][19][20][21]. We and others have previously reported on the functional effects of several SNPs in the MGMT P/E region [14,21].…”

Section: Introductionmentioning

confidence: 98%

MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression

Cross

Speidel

et al. 2016

Cell Oncol.

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“…Bisulfite modification prior to CpG pyrosequencing was performed to assess the percentage level of MGMT promoter methylation for each tumor spe cimen, as described previously (19). Chemically methylated or unmethylated universal human genomic DNA (EMD Millipore, Billerica, MA, USA) controls were included with each batch.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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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.

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“…Concomitant methylation of a panel of cancer-relevant genes including MGMT detected in lung epithelial cells present in sputum predicts risk for subsequent lung cancer incidence in moderate and heavy smokers (11,12). In addition, MGMT methylation is also a prognostic biomarker for response of glioblastoma patients to the alkylating agent temozolomide (13,14). …”

Section: Introductionmentioning

confidence: 99%

“…In addition to germline meQTL, somatic meQTL were also identified that affected the predisposition of cancer-relevant genes for promoter hypermethylation acquired in carcinogenesis for multiple tumor types (13,26–32). This is illustrated by our studies and others for MGMT methylation.…”

Section: Introductionmentioning

confidence: 99%

Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung

Leng

Collins

et al. 2015

Cancer Research

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O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that protects cells from carcinogenic effects of alkylating agents; however, MGMT is silenced by promoter hypermethylation during carcinogenesis. A single nucleotide polymorphism (SNP) in an enhancer in the MGMT promoter was previously identified to be highly significantly associated with risk for MGMT methylation in lung cancer and sputum from smokers. To further genetic investigations, a genome-wide association and replication study was conducted in two smoker cohorts to identify novel loci for MGMT methylation in sputum that were independent of the MGMT enhancer polymorphism. Two novel trans-acting loci (15q15.2 and 17q24.3) that were identified acted together with the enhancer SNP to empower risk prediction for MGMT methylation. We found that the predisposition to MGMT methylation arising from the 15q15.2 locus involved regulation of the ubiquitin protein ligase E3 component UBR1. UBR1 attenuation reduced turnover of MGMT protein and increased repair of O6-methylguanine in nitrosomethylurea-treated human bronchial epithelial cells (HBEC), while also reducing MGMT promoter activity and abolishing MGMT induction. Overall, our results substantiate reduced gene transcription as a major mechanism for predisposition to MGMT methylation in the lungs of smokers, and support the importance of UBR1 in regulating MGMT homeostasis and DNA repair of alkylated DNA adducts in cells.

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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

Cited by 55 publications

References 22 publications

MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression

MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression

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

Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung

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