<i>MGMT</i>Gene Silencing and Benefit from Temozolomide in Glioblastoma

Hegi, Monika E.; Diserens, Annie‐Claire; Gorlia, Thierry; Hamou, Marie‐France; Tribolet, Nicolas de; Weller, Michael; Kros, Johan M.; Hainfellner, Johannes A.; Mason, Warren P.; Mariani, Luigi; Bromberg, Jacoline E C; Hau, Peter; Mirimanoff, R.O.; Cairncross, J. Gregory; Janzer, Robert C.; Stupp, Roger

doi:10.1056/nejmoa043331

Cited by 6,446 publications

(5,306 citation statements)

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“…It also needs to be investigated whether CITED4 inactivation contributes to radio-and chemosensitivity or just represents a surrogate marker for other alterations in 1p/19q-deleted oligodendrogliomas. For example, 1p/19q-deletion has been linked to hypermethylation of the O 6 -methylguanine DNA methyltransferase (MGMT) gene (Mo¨llemann et al, 2005), which predicts response to alkylating chemotherapy in malignant gliomas (Hegi et al, 2005). Taken together, our results suggest CITED4 as an interesting novel candidate gene in oligodendroglial tumours and should stimulate further research into its functional roles and clinical significance.…”

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confidence: 71%

Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

et al. 2007

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Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and have been associated with sensitivity to radio-and chemotherapy as well as favourable prognosis. By using microarray-based expression profiling, we found that oligodendroglial tumours with 1p and 19q losses showed significantly lower expression of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 4 gene (CITED4) at 1p34.2 as compared to tumours without 1p and 19q losses. Mutational analysis showed no CITED4 mutations in gliomas. However, 1p and 19q losses as well as low expression of CITED4 transcripts were significantly associated with hypermethylation of the CITED4-associated CpG island. In line with the latter finding, treatment of CITED4 hypermethylated glioma cell lines with 5-aza-2 0 -deoxycytidine and trichostatine A resulted in a marked increase of the CITED4 transcript levels. Furthermore, CITED4 hypermethylation was significantly associated with longer recurrence-free and overall survival of patients with oligodendroglial tumours. Taken together, our results indicate that CITED4 is epigenetically silenced in the vast majority of oligodendroglial tumours with 1p and 19q deletions and suggest CITED4 hypermethylation as a novel prognostic marker in oligodendroglioma patients.

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confidence: 71%

Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

et al. 2007

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“…42,43 However, it is a predictive marker of a favorable outcome in patients with temozolomide-treated glioblastomas. [44][45][46][47] Temozolomide also reportedly enhances radiation responsiveness in MGMTnegative human glioblastoma cell lines. 48 …”

Section: Temozolomidementioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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“…Further molecular analysis showed a 46% 2‐year survival in a favorable subset of patients with epigenetic silencing of the O 6 ‐methylguanine‐DNA methyltransferase DNA‐repair gene. ( 13 – 15 ) …”

Section: Introductionmentioning

confidence: 99%

Intensity modulated radiation therapy versus three‐dimensional conformal radiation therapy for the treatment of high grade glioma: a dosimetric comparison

MacDonald

Ahmad

Kachris

et al. 2007

J Applied Clin Med Phys

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The present study compared the dosimetry of intensity‐modulated radiation therapy (IMRT) and three‐dimensional conformal radiation therapy (3D‐CRT) techniques in patients treated for high‐grade glioma. A total of 20 patients underwent computed tomography treatment planning in conjunction with magnetic resonance imaging fusion. Prescription dose and normal‐tissue constraints were identical for the 3D‐CRT and IMRT plans. The prescribed dose was 59.4 Gy delivered at 1.8 Gy per fraction using 4 – 10 MV photons. Normal‐tissue dose constraints were 50 – 54 Gy for the optic chiasm and nerves, and 55 – 60 Gy for the brainstem.The IMRT plan yielded superior target coverage as compared with the 3D‐CRT plan. Specifically, minimum and mean planning target volume cone down doses were 54.52 Gy and 61.74 Gy for IMRT and 50.56 Gy and 60.06 Gy for 3D‐CRT (p≤0.01). The IMRT plan reduced the percent volume of brainstem receiving a dose greater than 45 Gy by 31% (p=0.004) and the percent volume of brain receiving a dose greater than 18 Gy, 24 Gy, and 45 Gy by 10% (p=0.059), 14% (p=0.015), and 40% (p≤0.0001) respectively. With IMRT, the percent volume of optic chiasm receiving more than 45 Gy was also reduced by 30.40% (p=0.047). As compared with 3D‐CRT, IMRT significantly increased the tumor control probability (p≤0.005) and lowered the normal‐tissue complication probability for brain and brainstem (p<0.033).Intensity‐modulated radiation therapy improved target coverage and reduced radiation dose to the brain, brainstem, and optic chiasm. With the availability of new cancer imaging tools and more effective systemic agents, IMRT may be used to intensify tumor doses while minimizing toxicity, therefore potentially improving outcomes in patients with high‐grade glioma.PACs number: 87.53 Tf

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MGMTGene Silencing and Benefit from Temozolomide in Glioblastoma

Abstract: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

Cited by 6,446 publications

References 16 publications

Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q

Treatment of pituitary neoplasms with temozolomide

Intensity modulated radiation therapy versus three‐dimensional conformal radiation therapy for the treatment of high grade glioma: a dosimetric comparison

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