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A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.

ABSTRACT: Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.Genome-wide association analysis using ?2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P<10(-8)) with SNPs in the O(6)-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P<10(-26)) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas.The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations.

SUBMITTER: Brown CC

PROVIDER: S-EPMC3691078 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.

Brown Chad C CC Havener Tammy M TM Medina Marisa W MW Auman J Todd JT Mangravite Lara M LM Krauss Ronald M RM McLeod Howard L HL Motsinger-Reif Alison A AA

Pharmacogenetics and genomics 20121101 11

<h4>Objective</h4>Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.<h4>Methods</h4>In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.<h4>Results</h4>Genome-wide association analysis using ∼2.1 million quality-controlled single-nucleotide polym ...[more]

PMID: 23047291

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Project description:The prognosis for patients with glioblastoma (GB) remains grim. Concurrent temozolomide (TMZ) radiation-the cornerstone of glioma control-extends the overall median survival of GB patients by only a few months over radiotherapy alone. While these survival gains could be partly attributed to radiosensitization, this benefit is greatly minimized in tumors expressing O6-methylguanine DNA methyltransferase (MGMT), which specifically reverses O6-methylguanine lesions. Theoretically, non-O6-methylguanine lesions (i.e., the N-methylpurine adducts), which represent up to 90% of TMZ-generated DNA adducts, could also contribute to radiosensitization. Unfortunately, at concentrations attainable in clinical practice, the alkylation capacity of TMZ cannot overwhelm the repair of N-methylpurine adducts to efficiently exploit these lesions. The current therapeutic application of TMZ therefore faces two main obstacles: (i) the stochastic presence of MGMT and (ii) a blunted radiosensitization potential at physiologic concentrations. To circumvent these limitations, we are developing a novel molecule called NEO212-a derivatization of TMZ generated by coupling TMZ to perillyl alcohol. Based on gas chromatography/mass spectrometry and high-performance liquid chromatography analyses, we determined that NEO212 had greater tumor cell uptake than TMZ. In mouse models, NEO212 was more efficient than TMZ at crossing the blood-brain barrier, preferentially accumulating in tumoral over normal brain tissue. Moreover, in vitro analyses with GB cell lines, including TMZ-resistant isogenic variants, revealed more potent cytotoxic and radiosensitizing activities for NEO212 at physiologic concentrations. Mechanistically, these advantages of NEO212 over TMZ could be attributed to its enhanced tumor uptake presumably leading to more extensive DNA alkylation at equivalent dosages which, ultimately, allows for N-methylpurine lesions to be better exploited for radiosensitization. This effect cannot be achieved with TMZ at clinically relevant concentrations and is independent of MGMT. Our findings establish NEO212 as a superior radiosensitizer and a potentially better alternative to TMZ for newly diagnosed GB patients, irrespective of their MGMT status.

Project description:BackgroundThe use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated.MethodsFour nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2'-deoxycytidine was used to demethylate the MGMT promoter and O(6)-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed.ResultsOur results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229) and high (SF268 and SK-N-SH) basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines.ConclusionsThese results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma multiforme patients.

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A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.

Publications

A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.

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