Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Quillien, Véronique; Lavenu, Audrey; Karayan‐Tapon, Lucie; Carpentier, Catherine; Labussière, Marianne; Lesimple, Thierry; Chinot, Olivier; Wager, Michel; Honnorat, Jérôme; Saïkali, Stéphan; Fina, Frédéric; Sanson, Marc; Figarella‐Branger, Dominique

doi:10.1002/cncr.27392

Cited by 187 publications

(186 citation statements)

References 28 publications

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“…Methylation of MGMT promoter was associated with a prolonged overall survival in patients with glioblastoma receiving TEM (Hegi et al 2005). Among the available techniques to assess MGMT promoter methylation, pyrosequencing appears to be the most robust (Karayan-Tapon et al 2010, Quillien et al 2012. Similar findings regarding the predictive value of MGMT promoter methylation were suggested in PNETs (Schmitt et al 2014, Walter et al 2015.…”

Section: Introductionmentioning

confidence: 66%

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Cros

Hentic

Rebours

et al. 2016

Endocrine-Related Cancer

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Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O 6 -methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58 years (27-84)) with grade 1 WDPNET (n = 6) or 2 (n = 36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P = 0.04) and better progression-free survival (PFS) (HR = 0.35 (0.15-0.81), P = 0.01). Disease control rate at 18 months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR = 0.37 (0.29-1.08), P = 0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

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Section: Introductionmentioning

confidence: 66%

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Cros

Hentic

Rebours

et al. 2016

Endocrine-Related Cancer

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“…Pyrosequencing is a technology yielding accurate and highly reproducible knowledge about methylation percentages at a CpG (Tost & Gut 2007, Quillien et al 2012. By analysing normal adrenals and neoplasms, we could quantify to which extent methylation in tumours deviated from normal.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, DNA methylation is assessed by pyrosequencing, the most sensitive and accurate method to detect methylation at a single CpG (Quillien et al 2012). To the best of our knowledge, we analyse for the first time methylation in a number of different IGF2 regulatory regions in benign and malignant adrenal tumours.…”

Section: :9mentioning

confidence: 99%

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas

Creemers

Koetsveld

Kemenade

et al. 2016

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by realtime quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P < 0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997 ± 0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients.

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“…Pyrosequencing was performed with the PyroMark Q96 MGMT kit on a PSQTM96 MA system, as previously described. 20 All the reagents were from Qiagen, Courtaboeuf,…”

Section: Mgmt Analysismentioning

confidence: 99%

“…For data analysis, the average percentage of the five CpGs was determined and the cutoff set at 8%. 20 What's new? Glioblastoma (GBM) is considered to be one of the most radio-resistant types of tumor.…”

Section: Mgmt Analysismentioning

confidence: 99%

A concurrent ultra‐fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma

Beauchesne

Quillien

Faure

et al. 2015

Intl Journal of Cancer

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We report on a phase II clinical trial to determine the effect of a concurrent ultra-fractionated radiotherapy and temozolomide treatment in inoperable glioblastoma patients. A phase II study opened; patients over 18 years of age who were able to give informed consent and had histologically proven, newly diagnosed inoperable diagnosed and supratentorial glioblastoma were eligible. Three doses of 0.75 Gy spaced apart by at least 4 hr were delivered daily, 5 days a week for six consecutive weeks for a total of 67.5 Gy. Chemotherapy was administered during the same period, which consisted of temozolomide given at a dose of 75 mg/m 2 for 7 days a week. After a 4-week break, chemotherapy was resumed for up to six cycles of adjuvant temozolomide treatment, given every 28 days, according to the standard 5-day regimen. Tolerance and toxicity were the primary endpoints; survival and progression-free survival were the secondary endpoints. In total, 40 patients were enrolled in this study, 29 men and 11 women. The median age was 58 years, and the median Karnofsky performance status was 80. The concomitant ultra-fractionated radiotherapy and temozolomide treatment was well tolerated. Complete responses were seen in four patients, and partial responses were reported in seven patients. The median survival from the initial diagnosis was 16 months. Several long-term survivors were noted. Concurrent ultra-fractionated radiation therapy and temozolomide treatment are well accepted by the patients. The results showed encouraging survival rates for these unfavorable patients.Glioblastoma (GBM) is the most common primary brain tumor in adults and is characterized by a high rate of local recurrences because of its intrinsic radioresistance. 1-4 Indeed, GBM is considered one of the most radioresistant tumors.

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Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

Cited by 187 publications

References 28 publications

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas

A concurrent ultra‐fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma

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