Project description:Novel prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit either markers of proliferation or of angiogenesis and mesenchyme. Analysis of gene expression data is described in Phillips et al., Cancer Cell, 2006. Experiment Overall Design: 77 primary high-grade astrocytomas and 23 matched recurrences were profiled to identify changes in gene expression that relate to both survival and disease progression. Samples include WHO grade III and IV astrocytomas with a wide range of survival times.
Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage. 80 tumor samples, one normal tissue sample (brain)
Project description:Novel prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit either markers of proliferation or of angiogenesis and mesenchyme. Analysis of gene expression data is described in Phillips et al., Cancer Cell, 2006. Keywords: Disease state comparison
Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage.
Project description:High-grade glioma is the most aggressive form of primary brain tumor, characterized by rapid progression and a grim prognosis. The presence of mutations in the IDH1 and TP53 is associated with a specific molecular phenotype in glioma, and their interaction is a potential target for therapy.
Project description:Astrocytic tumors are known for their high progression capacity and for high mortality rates; in this regard, proteins correlated to prognosis can aid medical conduct. Although several genetic changes related to progression from low to high-grade astrocytoma are already known, mRNA copies do not necessarily correlate with protein abundance and, therefore could shadow further comprehension about this tumor’s biology. This motivates us to seek for complementary strategies to study tumor progression at the protein level. Here we compare the proteomic profile of biopsies from patients with low-grade (diffuse, n=6) versus high-grade astrocytoma (anaplastic and glioblastomas, n =10), using shotgun proteomics. Data analysis performed with PatternLab for proteomics identified 5,206 and 6,004 proteins in the low- and high-grade groups, respectively. Our results revealed seventy-four differentially abundant proteins (p < 0.01); we then shortlist those related to greater malignancy. We also describe molecular pathways distinctly activated in the two groups, such as differences in the organization of the extracellular matrix, decisive both in tumor invasiveness and in signaling for cell division, which, together with marked contrasts in energy metabolism, are determining factors in the speed of growth and dissemination of these neoplasms. The degradation pathways of GABA, enriched in the low-grade group, is consistent with a favorable prognosis. Other functions such as platelet degranulation, apoptosis, and activation of the MAPK pathway were correlated to high-grade tumors and, consequently, unfavorable prognoses. Our results provide an important survey of molecular pathways involved in glioma pathogenesis for these histopathological groups.
Project description:Gliomas are an incurable malignancy of the central nervous system. Patients that present with this disease have poor prognosis, necessitating the development of new therapeutic approaches. Glioblastoma is the most aggressive form of the disease and although lower grade gliomas have an intially better prognosis, they often progress to high grade glioma. Immunotherapy has been successful in other solid malignancies, but has not demonstrated efficacy in gliomas. Isocitrate dehydrogenase (IDH) is mutated in the majority of lower grade gliomas, and differences in the microenvironment between IDHmut and IDHwt disease contribute to differences in antitumor immunity. However, it remains unknown whether there are similiarites or differences between the immune landscape of IDHmut versus IDHwt gliomas. To address this question, we generated single-cell RNAseq data from 19 patients with grade II-IV glioma, of which 13 were IDHwt and 6 were IDHmut.
Project description:Gastric cancer, a leading cause of cancer related deaths, is a heterogeneous disease, with little consensus on molecular subclasses and their clinical relevance. We describe four molecular subtypes linked with distinct patterns of molecular alterations, disease progression and prognosis viz. a) Microsatellite Instable: hypermutated intestinal subtype tumors occurring in antrum, best overall prognosis, lower frequency of recurrence (22%), with liver metastasis in 23% of recurred cases b) Mesenchymal-like: diffuse tumors with worst prognosis, a tendency to occur at an earlier age and highest recurrence (63%) with peritoneal seeding in 64% of recurred cases, low frequency of molecular alterations c) TP53-inactive with TP53 loss, presence of focal amplifications and chromosomal instability d) TP53-active marked by EBV infection and PIK3CA mutations. The key molecular mechanisms and associated survival patterns are validated in multiple independent cohorts, to provide a consistent and unified framework for further preclinical and clinical research. ACRG Gastric cohort: microarray profiles from 300 gastric tumors from gastric cancer patients.
Project description:Combing WHO classification and molecular characteristics to analysis gliomas more and more important. But Grade III glioma samples have a big difference within the group had not been reported as far as we know. In this study, we proposed a model to evaluate diagnosis and prognosis of Grade III glioma patients, and two independent datasets indicated that the model has a good predictive ability. Therefore, this strategy provides a new method to assist diagnosis and treatment of Grade III glioma patients.