MOMC-3 - Yasin Mamatjan.mp4
MOMC-3 Hypermethylation and overexpression of HOX genes are poor prognosticators in Lower-Grade Glioma
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Yasin Mamatjan1, Mathew Voisin1, Farshad Nassiri1, Fabio Moraes2, Severa Bunda1, Mira Salih3, Kenneth Aldape4, Gelareh Zadeh1
1Princess Margaret Cancer Center, Toronto, Canada. 2Department of Oncology, Kingston, Canada. 3Boston Beth Israel Deaconess Medical Center, Boston, USA. 4Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, USA
Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability in patient outcome. To identify and characterize a predictive signature of outcome in diffuse gliomas, we utilized an integrative molecular analysis (methylation, mRNA, copy number variation (CNV) and mutation data) using multiple molecular platforms, including a total of 310 IDH mutant glioma samples from University Health Network (UHN) and German Cancer Research Center (DKFZ) together with 419 samples from The Cancer Genome Atlas (TCGA). Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival (p-value < 0.0001). The CpG‑based signatures were reliably validated using two independent datasets from TCGA and DKFZ cohorts (both p-values < 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. Further study in diffuse lower-grade glioma (LGG) using integrated mRNA and methylation (iRM) analyses showed that parallel HOX gene overexpression and hypermethylation in the same direction were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value < 0.0001). Furthermore, this iRM high group was characterized by a 7-HOX gene signature showed significant survival differences not only in IDH mutant LGG but also in IDH wildtype LGG. These results demonstrate the importance of HOX genes in predicting the outcome of diffuse gliomas to identify relevant molecular subtyping independent of histology.
Contact Presenter
Yasin Mamatjan1, Mathew Voisin1, Farshad Nassiri1, Fabio Moraes2, Severa Bunda1, Mira Salih3, Kenneth Aldape4, Gelareh Zadeh1
1Princess Margaret Cancer Center, Toronto, Canada. 2Department of Oncology, Kingston, Canada. 3Boston Beth Israel Deaconess Medical Center, Boston, USA. 4Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, USA
Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability in patient outcome. To identify and characterize a predictive signature of outcome in diffuse gliomas, we utilized an integrative molecular analysis (methylation, mRNA, copy number variation (CNV) and mutation data) using multiple molecular platforms, including a total of 310 IDH mutant glioma samples from University Health Network (UHN) and German Cancer Research Center (DKFZ) together with 419 samples from The Cancer Genome Atlas (TCGA). Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival (p-value < 0.0001). The CpG‑based signatures were reliably validated using two independent datasets from TCGA and DKFZ cohorts (both p-values < 0.0001). The results show that the methylation signatures that predict poor outcome also correlated with G-CIMP low status, elevated CNV instability and hypermethylation of a set of HOX gene probes. Further study in diffuse lower-grade glioma (LGG) using integrated mRNA and methylation (iRM) analyses showed that parallel HOX gene overexpression and hypermethylation in the same direction were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value < 0.0001). Furthermore, this iRM high group was characterized by a 7-HOX gene signature showed significant survival differences not only in IDH mutant LGG but also in IDH wildtype LGG. These results demonstrate the importance of HOX genes in predicting the outcome of diffuse gliomas to identify relevant molecular subtyping independent of histology.