scholarly journals 71. MGMT PROMOTER METHYLATION IS A PROGNOSTIC BIOMARKER IN EGFR MUTANT LUNG ADENOCARCINOMA WITH BRAIN METASTASES

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii15-ii15
Author(s):  
Yasin Mamatjan ◽  
Jeffrey Zuccato ◽  
Fabio Moraes ◽  
Michael Cabanero ◽  
Wumairehan Shali ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Promoter Methylation ◽  
Prognostic Biomarker ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Promoter Methylation Status ◽  
Mgmt Promoter ◽  
Egfr Mutant ◽  
Mgmt Promoter Methylation Status

Abstract EGFR-mutant lung adenocarcinomas (EGFRm-LUAD) have a higher risk of brain metastasis (BM) development than non-mutant lesions regardless of cancer stage. BM development is a marker of tumor aggressiveness and has significant prognostic impact that leads to treatment failure. MGMT promoter methylation is known to determine response to therapy in other cancer types but it has not been investigated in EGFRm-LUAD brain metastases. This work aims to assess whether MGMT promoter methylation predicts patient survival or BM development in EGFRm-LUAD patients. A large cohort of 90 primary EGFRm-LUAD, 33(37%) of which developed BM, were profiled using Illumina Infinium MethylationEPIC Beadchip. We utilized genome-wide methylation signatures to determine MGMT methylation status using the previously reported MGMT-STP27 approach that uses two CpG sites to predict MGMT methylation status. Cox modeling was performed to assess whether MGMT methylation status correlates with overall survival independent of other clinical factors. MGMT methylation significantly predicted poorer survival in EGFRm-LUAD patients developed BM (p=0.0003) and those who did not (p=0.003). A multivariate Cox analysis, adjusting for stage and smoking status as potential confounders, showed that MGMT methylation (HR=6.2, 95%CI:2.2–17.4, p=0.0005) and BM (HR=2.6, 95%CI:1.3–5.3, p=0.007) were both independently predictive of worsened survival. Total Mutation Burden calculated by the number of mutations per megabase of DNA was higher in MGMT methylated tumours with an interquartile range (IQR) of 58(30–71) compared to MGMT unmethylated tumours with IQR of 5.5(4.3–6.1). This work shows that MGMT promoter methylation status is an important prognostic biomarker in EGFRm-LUAD patients. Further work will validate these findings obtained using whole-genome DNA methylation by comparing to results using methylation specific PCR assays. MGMT promoter methylation status in EGFRm–LUAD patients with BM may be used to guide patient treatment with potentially a greater extent of treatment for those higher risk patients.

scholarly journals BIOM-02. IDENTIFYING MGMT ALTERATIONS AS BIOMARKERS OF SURVIVAL IN LUNG ADENOCARCINOMA WITH BRAIN METASTASES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii1-ii1
Author(s):  
Yasin Mamatjan ◽  
Jeffrey Zuccato ◽  
Fabio Moraes ◽  
Michael Cabanero ◽  
Wumairehan Shali ◽  
...  
Keyword(s):  
Overall Survival ◽  
Brain Metastases ◽  
Promoter Methylation ◽  
Patient Survival ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Mgmt Promoter ◽  
Egfr Mutant ◽  
Mgmt Promoter Methylation Status

Abstract EGFR-mutant lung adenocarcinomas (EGFRm-LUAD) have a higher risk of developing brain metastases (BM) compared to non-EGFR-mutant tumors. BM development has significant prognostic impact and leads to poorer patient survival. MGMT promoter methylation is known to determine response to therapy in other cancer types including intracranial gliomas but has not been investigated in EGFRm-LUAD BM. This work aims to assess whether MGMT promoter methylation predicts patient survival or BM development in EGFRm-LUAD patients. A large cohort of 90 primary EGFRm-LUAD tumors, of which 33 (37%) developed BM, were profiled using the Illumina Infinium MethylationEPIC Bead chip. Using the previously reported MGMT-STP27 approach that uses two CpG sites to predict MGMT methylation status, Cox modeling was performed to assess whether MGMT methylation status correlates with overall survival independent of other clinical factors. MGMT methylation significantly predicted poorer survival in EGFRm-LUAD patients that developed BM (p=0.0003) and did not develop BM (p=0.003). A multivariate cox analysis, adjusting for cancer stage and smoking status as potential confounders, showed that MGMT methylation (HR=6.2, 95%CI:2.2–17.4, p=0.0005) and BM development (HR=2.6, 95%CI:1.3–5.3, p=0.007) were both independently predictive of worse overall survival in EGFRm-LUAD patients. This finding of poorer survival in MGMT methylated EGFRm-LUAD is validated in an independent LUAD patient cohort. Total mutation burden, calculated by the number of mutations per megabase of DNA, was substantially higher in MGMT methylated tumours with an interquartile range (IQR) of 58 (30–71) compared to MGMT unmethylated tumours with the IQR of 5.5 (4.3–6.1) resulting p-value of 0.01 for this comparison. Overall, this work shows that MGMT promoter methylation status is an important prognostic biomarker in LUAD patients. MGMT promoter methylation status in EGFRm–LUAD patients with BM may be used to guide patient treatment with potentially a greater extent of treatment for high-risk patients.

scholarly journals XGBoost Improves Classification of MGMT Promoter Methylation Status in IDH1 Wildtype Glioblastoma

2020 ◽  
Vol 10 (3) ◽  
pp. 128 ◽  
Author(s):  
Nguyen Quoc Khanh Le ◽  
Duyen Thi Do ◽  
Fang-Ying Chiu ◽  
Edward Kien Yee Yapp ◽  
Hui-Yuan Yeh ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Gradient Boosting ◽  
Mgmt Methylation ◽  
Promoter Methylation Status ◽  
Extreme Gradient Boosting ◽  
Mgmt Promoter ◽  
Mgmt Promoter Methylation Status

Approximately 96% of patients with glioblastomas (GBM) have IDH1 wildtype GBMs, characterized by extremely poor prognosis, partly due to resistance to standard temozolomide treatment. O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a crucial prognostic biomarker for alkylating chemotherapy resistance in patients with GBM. However, MGMT methylation status identification methods, where the tumor tissue is often undersampled, are time consuming and expensive. Currently, presurgical noninvasive imaging methods are used to identify biomarkers to predict MGMT methylation status. We evaluated a novel radiomics-based eXtreme Gradient Boosting (XGBoost) model to identify MGMT promoter methylation status in patients with IDH1 wildtype GBM. This retrospective study enrolled 53 patients with pathologically proven GBM and tested MGMT methylation and IDH1 status. Radiomics features were extracted from multimodality MRI and tested by F-score analysis to identify important features to improve our model. We identified nine radiomics features that reached an area under the curve of 0.896, which outperformed other classifiers reported previously. These features could be important biomarkers for identifying MGMT methylation status in IDH1 wildtype GBM. The combination of radiomics feature extraction and F-core feature selection significantly improved the performance of the XGBoost model, which may have implications for patient stratification and therapeutic strategy in GBM.

MGMT promoter methylation status in brain metastases from colorectal cancer and corresponding primary tumors

2015 ◽  
Vol 11 (8) ◽  
pp. 1201-1209 ◽  
Author(s):  
Giovanna De Maglio ◽  
Mariaelena Casagrande ◽  
Michela Guardascione ◽  
Caterina Fontanella ◽  
Stefania Eufemia Lutrino ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Brain Metastases ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Primary Tumors ◽  
Promoter Methylation Status ◽  
Mgmt Promoter ◽  
Mgmt Promoter Methylation Status

scholarly journals NIMG-38. NON-INVASIVE PREDICTION OF MGMT PROMOTER METHYLATION USING COMBINED FET PET/MRI RADIOMICS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii156-ii156
Author(s):  
Philipp Lohmann ◽  
Anna-Katharina Meissner ◽  
Jan-Michael Werner ◽  
Gabriele Stoffels ◽  
Martin Kocher ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Test Dataset ◽  
Fet Pet ◽  
Promoter Methylation Status ◽  
Non Invasive ◽  
Mgmt Promoter ◽  
Amino Acid Pet ◽  
Mgmt Promoter Methylation Status

Abstract BACKGROUND Recently, the Response Assessment in Neuro-Oncology (RANO) Working Group emphasized the additional diagnostic value of amino acid PET in addition to MRI. However, the number of studies using amino acid PET/MRI radiomics is still low. We investigated the potential of combined O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET/MRI radiomics for the non-invasive prediction of the O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation status in glioma patients. METHODS Seventy-one patients with newly diagnosed glioma (predominantly WHO grade III and IV glioma, 82%) underwent a hybrid FET PET/MRI scan. Forty-six patients (65%) had a methylated MGMT promoter. The tumor and tumor subregions were manually segmented on conventional MRI. In total, 199 standardized features were obtained from FET PET, contrast-enhanced T1-weighted, T2-weighted, and fluid attenuated inversion recovery (FLAIR) MRI. After feature extraction and data normalization, patients were randomly assigned to a training and a test dataset for final model evaluation in a ratio of 70/30, with a balanced distribution of the MGMT promoter methylation status. Feature selection was performed by recursive feature elimination using random forest regressors. For the final model generation, the number of features was limited to seven to avoid data overfitting. Different algorithms for model generation were compared, and the model performance in the training data was assessed by 5-fold cross-validation. Finally, the best performing models were applied to the test dataset to evaluate the robustness of the models. RESULTS In the test dataset, the best radiomics signatures obtained from MRI or FET PET alone achieved diagnostic accuracies for the prediction of the MGMT promoter methylation of 64% and 70%, respectively. In contrast, the highest diagnostic accuracy of 83% was obtained by combining FET PET and MRI features. CONCLUSION Combined FET PET/MRI radiomics allows the non-invasive prediction of the MGMT promoter methylation status in patients with gliomas, providing more diagnostic information than either modality alone.

scholarly journals MGMT Promoter Methylation and Parathyroid Carcinoma

2019 ◽  
Vol 3 (11) ◽  
pp. 2114-2122
Author(s):  
Sara Storvall ◽  
Eeva Ryhänen ◽  
Ilkka Heiskanen ◽  
Tiina Vesterinen ◽  
Frank V Bensch ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Parathyroid Adenoma ◽  
Promoter Methylation ◽  
Parathyroid Carcinoma ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Promoter Methylation Status ◽  
Mgmt Promoter ◽  
Atypical Parathyroid Adenoma ◽  
Mgmt Promoter Methylation Status

Abstract Context Parathyroid carcinoma (PC) is extremely rare. Prognosis is poor, with no known evidence-based systemic therapies. We previously reported complete remission in a patient with metastasized parathyroid carcinoma and high tumor MGMT promoter methylation status who was treated with temozolomide. Objective To study MGMT promoter methylation status in an additional set of aggressive parathyroid tumors. Design/Setting The study included 12 patients: 7 with sporadic and 5 with familial primary hyperparathyroidism (two of the latter carried a CDC73 gross deletion). Patient 9 is the previously described patient with PC and high MGMT methylation status. Her daughter (patient 12) had surgery for severe primary hyperparathyroidism due to atypical parathyroid adenoma during pregnancy. Eleven patients thus had PC and one had atypical parathyroid adenoma. MGMT promoter methylation status was determined from DNA extracted from primary (n = 10) or metastatic (n = 2) tumors. A mean methylation level >20% was considered high. Patient 11 had metastatic PC and received temozolomide cycles. Results Only the previously published patient (patient 9) had high tumor MGMT promoter methylation status. This was not a characteristic of the atypical parathyroid adenoma of the daughter (patient 12). Patient 11 (CDC73 intragenic deletion) has disseminated PC, low MGMT promoter methylation, and stable disease on follow-up after temozolomide treatment. Conclusion High MGMT promoter methylation status seems rare in PC. However, as demonstrated in other neuroendocrine tumors, some patients with disseminated PC might benefit from temozolomide. Demonstration of high methylation status could be a predictor of positive response to temozolomide treatment.

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