Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: IDH2 (cancer-related)
Stegmann S, Werner JM, Kuhl S, et al.Death Receptor 6 (DR6) Is Overexpressed in Astrocytomas.
Anticancer Res. 2019; 39(5):2299-2306 [PubMed
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BACKGROUND/AIM: Death receptor 6 (DR6) is a member of the tumor necrosis factor receptor superfamily. The expression of DR6 is elevated in different kinds of tumors including ovarian, breast cancer and adult sarcoma. In these tumors, the receptor may be handled as a new diagnostic and prognostic marker. Thus, we investigated the expression of DR6 in gliomas.
MATERIALS AND METHODS: Tumor and control tissues were extracted during neurosurgery and grouped according to the WHO classification. DR6 expression was investigated in low- and high-grade gliomas PCR (n=70), immunofluorescence staining (n=33) and western blot (n=58). Additional analysis of TCGA-data was performed to assess the general alteration of DR6 in cancer and influence of IDH-mutation on DR6 expression in gliomas.
RESULTS: The expression of DR6 was significantly enhanced in gliomas (p<0.05). It showed a trend towards rising expression with increasing malignancy of the tumor. Chemotherapy treatment could have an influence on DR6 expression.
CONCLUSION: In our investigation, DR6 acts as a potential suitable diagnostic marker for gliomas.
Malzkorn B, Reifenberger GIntegrated diagnostics of diffuse astrocytic and oligodendroglial tumors.
Pathologe. 2019; 40(Suppl 1):9-17 [PubMed
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BACKGROUND: Diffuse astrocytic and oligodendroglial gliomas are the most common neuroepithelial tumors. Their classification is based on the integration of histological and molecular findings according to the classification of tumors of the central nervous system published by the World Health Organization (WHO) in 2016.
OBJECTIVES: This review describes the different entities and variants of diffuse gliomas and summarizes the current diagnostic criteria for these tumors.
MATERIALS AND METHODS: Based on the 2016 WHO classification and selected other publications, the histomolecular diagnostics of diffuse gliomas is presented and illustrated.
RESULTS: Diffuse gliomas are divided into isocitrate dehydrogenase (IDH)-mutant or IDH-wildtype gliomas by detection of mutations in the IDH1 or IDH2 genes. Among the IDH-mutant gliomas, oligodendroglial tumors are characterized by combined losses of chromosome arms 1p and 19q. Loss of nuclear expression of the ATRX protein is a marker of IDH- mutant astrocytic gliomas. Glioblastoma, IDH-wildtype, is the most common diffuse glioma. Diffuse and anaplastic astrocytic gliomas without IDH mutation should be further evaluated for molecular features of glioblastoma, IDH-wildtype. Diffuse gliomas in the thalamus, brainstem, or spinal cord carrying a histone 3 (H3)-K27M mutation are classified as diffuse midline gliomas, H3-K27M-mutant. By determining the IDH and 1p/19q status, oligoastrocytomas can be stratified into either astrocytic or oligodendroglial gliomas. Gliomatosis cerebri is no longer regarded as a distinct glioma entity.
CONCLUSIONS: Diffuse gliomas can today be classified accurately and reproducibly by means of histological, immunohistochemical, and molecular analyses.
Xue YM, Cheng HC, Wang JH, et al.Cytosine 5-hydroxymethylation regulated kit gene expression in acute myeloid leukemia.
J Biol Regul Homeost Agents. 2019 Mar-Apr; 33(2):345-353 [PubMed
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5-methyl cytosine (5mC) can be oxidized to 5-hydroxymethyl cytosine (5hmC) under the action of TET protein family, and 5hmC plays important roles in the pathogenesis of various tumors including acute myeloid leukemia (AML). In this study, we evaluated the role of 5mC and 5hmC levels in HL60 AML cells and bone marrow samples from AML patients for KIT gene expression to analyze 5hmC level in AML pathogenesis. Results showed that the expression and 5hmC level increased significantly of the KIT gene but the change of its 5mC level was not obvious after being treated by decitabine (DAC) in HL60 cells. IDH1 and IDH2 expression increased followed by increased KIT 5hmC level. In AML patients with IDH1 or IDH2 mutation, KIT expression and 5hmC were much lower than in those without mutation. The study indicated that the expression of KIT gene was regulated by 5hmC level in HL60 cells, and the 5hmC level was regulated by IDH1 and IDH2.
Innate immunity plays a central role in neoplasms, including those affecting the central nervous system (CNS). Nowadays, tumors classification, especially that regarding gliomas, is based on molecular features such as mutations in isocitrate dehydrogenase (IDH) genes and the presence of co-deletion 1p/19q. Therapy, in most cases, is based on surgery, radiotherapy, and pharmacological treatment with chemotherapeutic agents such as temozolomide. However, the results of the treatments, after many decades, are not completely satisfactory. There is a class of drugs, used to treat cancer, which modulates immune response; in this class, the immune checkpoint inhibitors and vaccines play a prominent role. These drugs were evaluated for the treatment of gliomas, but they exhibited a poor outcome in clinical trials. Those scarce results could be due to the response of tumor-associated macrophage that creates imbalances between innate and adaptive immunity and changes in blood-brain barrier properties. Here, we have briefly reviewed the current literature on this topic, focusing on the possible role for innate immunity in the failure of immunotherapies against brain tumors.
Rao S, Kanuri NN, Nimbalkar V, et al.High frequency of H3K27M immunopositivity in adult thalamic glioblastoma.
Neuropathology. 2019; 39(2):78-84 [PubMed
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Adult thalamic glioblastomas (GBM) are uncommon tumors with limited available molecular data. One of the reported molecular alterations in these tumors is the H3K27M mutation. It has been documented that H3K27M mutation is found in a high proportion of pediatric thalamic gliomas. In this study, we have analyzed the molecular alterations exclusive to adult thalamic GBM. This is a 6 years retrospective study of adult thalamic GBM patients who underwent surgical decompression of the tumor. Clinical data were obtained from the case records. Immunohistochemistry (IHC) was performed on the tumors using antibodies directed against the gene products of R132H mutant isocitrate dehydrogenase 1 (IDH1), alpha-thalassemia/mental retardation X-linked (ATRX), p53, H3K27M, H3K27me3, and V600E mutant BRAF. Molecular analyses were carried out to detect other IDH1 and IDH2 mutations, O
Aoki K, Natsume AOverview of DNA methylation in adult diffuse gliomas.
Brain Tumor Pathol. 2019; 36(2):84-91 [PubMed
] Related Publications
Adult diffuse gliomas form a heterogeneous group of tumors of the central nervous system that vary greatly in histology and prognosis. A significant advance during the last decade has been the identification of a set of genetic lesions that correlate well with histology and clinical outcome in diffuse gliomas. Most characteristic driver mutations consist of isocitrate dehydrogenase 1 (IDH1) and IDH2, and H3 histone family member 3A, which are strongly associated with DNA and histone methylation patterns. A well-characterized DNA methylation aberration is on the O6-methylguanine-DNA methyltransferase promoter. This aberration is associated with an improved response to the DNA alkylating agent, temozolomide. Methylation alterations are used for classification or treatment decisions of diffuse gliomas. This supports the importance of considering epigenomic aberrations in the pathogenesis of gliomas. Recent DNA methylation analyses revealed a small group of IDH mutant diffuse gliomas exhibiting decreased DNA hypermethylation resulting in substantial unfavorable prognosis comparable to glioblastoma. Thus, DNA methylation patterns may become a new standard that replaces the conventional grading system based on histological diagnosis. In this review, we summarize recent developments regarding the contributions of methylation patterns to the pathogenesis of adult diffuse glioma, the interactions between methylation patterns and driver mutations, and potential epigenomic targeted therapies.
Chai Y, Liu W, Wang C, et al.Prognostic Role of Chicken Ovalbumin Upstream Promoter Transcription Factor II in Isocitrate Dehydrogenase-Mutant Glioma with 1p19q Co-Deletion.
J Mol Neurosci. 2019; 68(2):234-242 [PubMed
] Related Publications
BACKGROUND: Chicken ovalbumin upstream promoter transcription factor II is known to play a crucial role in the tumor microenvironment. However, the role of NR2F2 in gliomas is unknown.
METHODS: The genomic and clinical data of 530 cases of lower grade gliomas (LGGs) patients and 167 cases of glioblastoma (GBM) patients in The Cancer Genome Atlas (TCGA) were extracted for analysis. R2 and UCSC Xena browser were used for Kaplan-Meier survival in the GSE16011 dataset and TCGA dataset, respectively. GraphPad Prism 7 was used to compare the differences in NR2F2 expression between various groups and subtypes.
RESULTS: LGG patients with low NR2F2 expression had a significantly favorable outcome compared with those with high NR2F2 expression (p < 0.05). By matching histological subtypes and gene expression profiles of LGG patients, grade II glioma group showed lowest levels of NR2F2 expression compared with grade III gliomas and GBM. Patients diagnosed with astrocytoma have highest expression of NR2F2 but lowest OS (p < 0.05). In LGGs, NR2F2 expression was significantly downregulated in patient group with IDH mutation and 1p19q co-deletion (p < 0.05).
CONCLUSION: Our study suggests that NR2F2 can be used as a prognostic marker in LGG patients with IDH mutation and 1p19 co-deletion.
Huang R, Liao X, Li J, et al.Genome-scale integrated analysis to identify prospective molecular mechanisms and therapeutic targets in isocitrate dehydrogenase 2 R140Q-mutated acute myeloid leukemia.
Oncol Rep. 2019; 41(5):2876-2888 [PubMed
] Free Access to Full Article Related Publications
The aim of the present study was to identify potential molecular mechanisms and therapeutic targets in regards to isocitrate dehydrogenase 2 (IDH2) R140Q-mutated acute myeloid leukemia (AML). An RNA sequencing dataset of IDH2 wild-type and R140Q-mutated adult de novo AML bone marrow samples was obtained from The Cancer Genome Atlas (TCGA) database. The edgeR package was used to screen for the differentially expressed genes (DEGs), and the potential molecular mechanisms and therapeutic targets were identified using Database for Annotation, Visualization, and Integrated Discovery (DAVID) v6.8, Biological Networks Gene Ontology tool, Connectivity Map (CMap), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and GeneMANIA. A total of 230 DEGs were identified between the bone marrow tissues of IDH2 R140Q-mutated and wild-type AML patients, of which 31 were significantly associated with overall survival (OS). Functional assessment of DEGs showed significant enrichment in multiple biological processes, including angiogenesis and cell differentiation. STRING and GeneMANIA were used to identify the hub genes of these DEGs. CMap analysis identified 13 potential small-molecule drugs against IDH2 R140Q-mutated adult de novo AML. Genome-wide co-expression network analysis identified several IDH2 R140Q co-expressed genes, of which 56 were significantly associated with AML OS. The difference in IDH2 mRNA expression levels and OS between the IDH2 R140Q-mutated and wild-type AML were not statistically significant in our cohort. In conclusion, we identified several co-expressing genes and potential molecular mechanisms that are instrumental in IDH2 R140Q-mutated adult de novo AML, along with 13 candidate targeted therapeutic drugs.
Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer's, Parkinson's, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety. A common conformational variation of these IDPs is misfolding and aggregation, forming, for instance, neurotoxic amyloid plaques. In this review, we discuss some IDPs that are involved in neurodegenerative diseases (such as beta amyloid, alpha synuclein, tau, and the "IDP-like" PrP), cancer (p53, c-Myc), and diabetes (amylin), focusing on the structural changes of these IDPs that are linked to such pathologies. We also present the IDP modulation mechanisms that can be explored in new strategies for drug design. Lastly, we show some candidate drugs that can be used in the future for the treatment of diseases caused by misfolded IDPs, considering that cancer therapy has more advanced research in comparison to other diseases, while also discussing recent and future developments in this area of research. Therefore, we aim to provide support to the study of IDPs and their modulation mechanisms as promising approaches to combat such severe diseases.
Sonoda Y, Yokoo H, Tanaka S, et al.Practical procedures for the integrated diagnosis of astrocytic and oligodendroglial tumors.
Brain Tumor Pathol. 2019; 36(2):56-62 [PubMed
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The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. However, many pathologists in Japan cannot diagnose astrocytic or oligodendroglial tumors according to the 2016 WHO CNS due to financial or technical problems. Therefore, the Japan Society of Brain Tumor Pathology established a committee for molecular diagnosis to facilitate the integrated diagnosis of astrocytic and oligodendroglial tumors in Japan. We created three levels of diagnoses: Level 1 was defined as simple histopathological diagnosis using hematoxylin and eosin staining and routine cell lineage-based immunostaining. Level 2 was defined as immunohistochemical diagnosis using immunohistochemical examinations using R132H mutation-specific IDH1, ATRX, and/or p53 antibodies. Level 3 was defined as molecular diagnosis, such as diagnosis based on 1p/19q status or the mutation status of the IDH1 and IDH2 genes. In principle, astrocytic and oligodendroglial tumors should be diagnosed based on the 2016 WHO CNS and/or cIMPACT-NOW criteria; however, the findings obtained through our diagnostic flowchart can be added to the histological diagnosis in parentheses. This classification system would be helpful for pathologists with limited resources.
BACKGROUND: IDH1/2 mutated glioma has been associated with a germline risk variant, the rs55705857 G allele. The Utah Population Database (UPDB), a computerized genealogy of people in Utah, is a unique resource to evaluate cancer risk in related individuals.
METHODS: One hundred and two individuals with IDH1/2 mutant or 1p/19q co-deleted glioma were genotyped and linked to the UPDB. DNA came from blood (21), tumor tissue (43), or both (38). We determined congruence between somatic and germline samples and estimated the relative risk for developing cancer to first and second-degree relatives of G and A allele carriers at rs55705857.
RESULTS: Somatic (glioma) DNA had 85.7% sensitivity (CI 57.2-98.2%) and 95.8% specificity (CI 78.9-99.89%) for germline rs55705857 G allele. Forty-one patients were linked to pedigrees in the UPDB with at least three generations of data. First-degree relatives of rs55705857 G allele carriers were at significantly increased risk for developing cancer (RR = 1.72, p = 0.045, CI 1.02-2.94), and specifically for oligodendroglioma (RR = 57.61, p = 0.017, CI 2.96-320.98) or prostate cancer (RR = 4.10, p = 0.008, CI 1.62-9.58); relatives of individuals without the G allele were not at increased risk. Second-degree relatives of G allele carriers also had significantly increased risk for developing cancer (RR = 1.50, p = 0.007, CI 1.15-2.01).
CONCLUSIONS: Tumor DNA may approximate genotype at the rs55705857 locus. We confirmed this locus confers an increased risk of all cancers and especially of oligodendroglioma. No increased cancer or brain tumor risk is seen in family members of individuals without the high-risk G allele.
BACKGROUND: Cancer cells use specific V-ATPase subunits to activate oncogenic pathways. Therefore, we investigated V-ATPase deregulation in aggressive gliomas and associated signaling.
METHODS: V-ATPase genes expression and associated pathways were analyzed in different series of glioma available from public databases, as well as in patients' cohort. Activation of pathways was analyzed at gene and protein expression levels. A genetic model of glioma in Drosophila melanogaster and mice with GBM patients-derived orthotopic xenografts were used as in vivo models of disease.
FINDINGS: GBM and recurrent gliomas display a specific V-ATPase signature. Such signature resolves the heterogeneous class of IDH-wild type lower-grade gliomas, identifying the patients with worse prognosis independently from clinical and molecular features (p = 0·03, by Cox proportional-hazards model). In vivo, V-ATPase subunits deregulation significantly impacts tumor growth and proliferation. At the molecular level, GBM-like V-ATPase expression correlates with upregulation of Homeobox genes.
INTERPRETATION: Our data identify a V-ATPase signature that accompanies glioma aggressiveness and suggest new entry points for glioma stratification and follow-up. FUND: This work was supported by Fondazione Cariplo (2014-1148 to VV), Fondazione IRCCS Ca' Granda, and Fondazione INGM Grant in Molecular Medicine 2014 (to VV).
Benard B, Gentles AJ, Köhnke T, et al.Data mining for mutation-specific targets in acute myeloid leukemia.
Leukemia. 2019; 33(4):826-843 [PubMed
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Three mutation-specific targeted therapies have recently been approved by the FDA for the treatment of acute myeloid leukemia (AML): midostaurin for FLT3 mutations, enasidenib for relapsed or refractory cases with IDH2 mutations, and ivosidenib for cases with an IDH1 mutation. Together, these agents offer a mutation-directed treatment approach for up to 45% of de novo adult AML cases, a welcome deluge after a prolonged drought. At the same time, a number of computational tools have recently been developed that promise to further accelerate progress in mutation-specific therapy for AML and other cancers. Technical advances together with comprehensively annotated AML tissue banks have resulted in the availability of large and complex data sets for exploration by the end-user, including (i) microarray gene expression, (ii) exome sequencing, (iii) deep sequencing data of sub-clone heterogeneity, (iv) RNA sequencing of gene expression (bulk and single cell), (v) DNA methylation and chromatin, (vi) and germline quantitative trait loci. Yet few clinicians or experimental hematologists have the time or the training to access or analyze these repositories. This review summarizes the data sets and bioinformatic tools currently available to further the discovery of mutation-specific targets with an emphasis on web-based applications that are open, accessible, user-friendly, and do not require coding experience to navigate. We show examples of how available data can be mined to identify potential targets using synthetic lethality, drug repurposing, epigenetic sub-grouping, and proteomic networks while also highlighting strengths and limitations and the need for superior models for validation.
Latysheva A, Emblem KE, Brandal P, et al.Dynamic susceptibility contrast and diffusion MR imaging identify oligodendroglioma as defined by the 2016 WHO classification for brain tumors: histogram analysis approach.
Neuroradiology. 2019; 61(5):545-555 [PubMed
] Related Publications
PURPOSE: According to the revised World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) of 2016, oligodendrogliomas are now defined primarily by a specific molecular signature (presence of IDH mutation and 1p19q codeletion). The purpose of our study was to assess the value of dynamic susceptibility contrast MR imaging (DSC-MRI) and diffusion-weighted imaging (DWI) to characterize oligodendrogliomas and to distinguish them from astrocytomas.
METHODS: Seventy-one adult patients with untreated WHO grade II and grade III diffuse infiltrating gliomas and known 1p/19q codeletion status were retrospectively identified and analyzed using relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) maps based on whole-tumor volume histograms. The Mann-Whitney U test and logistic regression were used to assess the ability of rCBV and ADC to differentiate between oligodendrogliomas and astrocytomas both independently, but also related to the WHO grade. Prediction performance was evaluated in leave-one-out cross-validation (LOOCV).
RESULTS: Oligodendrogliomas showed significantly higher microvascularity (higher rCBV
CONCLUSION: Histogram-derived rCBV and ADC parameter may be used as biomarkers for identification of oligodendrogliomas and may help characterize diffuse gliomas based upon their genetic characteristics.
Na K, Kim HS, Shim HS, et al.Targeted next-generation sequencing panel (TruSight Tumor 170) in diffuse glioma: a single institutional experience of 135 cases.
J Neurooncol. 2019; 142(3):445-454 [PubMed
] Related Publications
PURPOSE: The TruSight Tumor 170 (TST-170) panel consists of a DNA workflow for the identification of single-nucleotide variants, small insertions and deletions, and copy number variation, as well as a panel of 55 genes for a RNA workflow for the identification of splice variants and gene fusions. To date, the application of TST-170 in diffuse gliomas (DGs) has not been described.
METHODS: We analyzed 135 samples of DG, which were diagnosed by WHO criteria based on histological features and conventional molecular tests including immunostaining, 1p/19q FISH, and analysis of MGMT methylation and TERT promoter mutation.
RESULTS: A total of 135 cases consisted of 38 IDH-mutant [17 astrocytoma (AC), 13 oligodendroglioma (OD) and eight glioblastoma (GBM)], 87 IDH-wildtype (six AC, three OD and 78 GBM), and 10 diffuse midline glioma, H3K27M-mutant. DNA analysis enabled the detection of all mutations identified in these samples by conventional techniques, and the results were highly comparable to the known mutations in each subtype. RNA analysis detected four fusion genes including PTPRZ1-MET, FGFR3-TACC3, FAM131B-BRAF, and RET-CCDC6 and one splicing variant (EGFR vIII mutant). Clustered copy number loss in 1p and 19q loci genes were detected in 1p/19q-codeleted OD.
CONCLUSIONS: The application of TST-170 panel based NGS in clinical and laboratory setting is expected to improve diagnostic accuracy and prognostication. Most benefits are expected in IDH-wildtype DG, a group of genetically heterogenous tumors harboring DNA sequence changes, copy number alterations, and fusions in a large number of oncogenes and tumor suppressor genes.
Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy
RATIONALE: Glioblastomas are malignant, infiltrating gliomas classified as grade IV by the World Health Organization. Genetically, most glioblastomas do not exhibit the isocitrate dehydrogenase (IDH) 1/2 gene mutation and rarely harbor the 1p/19q co-deletion. Neuroradiologically, glioblastomas rarely form a cyst with a mural nodule lesion.
PATIENT CONCERNS: In this study, a 78-year-old woman, with speech difficulty and forgetfulness, had a cystic tumor with a mural nodule in the right frontoparietal lobe. Therefore, partial tumor resection was performed.
DIAGNOSIS: Histopathology of the tumor, a glioblastoma, exhibited pseudopapillary features with non-hyalinized capillary cores and rich mini-gemistocytic cells. Genetic analysis of the tumor revealed co-deletion of 1p36/19q13, with wild-type IDH.
INTERVENTIONS: The patient underwent a combination of postoperative radiotherapy and temozolomide chemotherapy before leaving the hospital. After discharge, she was treated by 20 courses of temozolomide chemotherapy.
OUTCOMES: The patient is free from tumor recurrence 23 months after the operation.
LESSONS: We present a unique case of glioblastoma that exhibited novel neuroradiological, histopathological, and genetic features with a favorable prognosis for the patient. Therefore, a compilation of similar cases with clinicopathological and genetic analyses to characterize this unique glioblastoma is critical. Clinical evidence will help develop effective therapeutic approaches to improve prognosis in patients with glioblastoma.
Masui K, Onizuka H, Cavenee WK, et al.Metabolic reprogramming in the pathogenesis of glioma: Update.
Neuropathology. 2019; 39(1):3-13 [PubMed
] Related Publications
Cancer is a genetic disease that is currently classified not only by its tissue and cell type of origin but increasingly by its molecular composition. Increasingly, tumor classification and subtyping is being performed based upon the oncogene gains, tumor suppressor losses, and associated epigenetic and transcriptional features. However, cancers, including brain tumors, are also characterized by profound alterations in cellular metabolism. At present, even though signature mutations in known metabolic enzymes are recognized as being important, the metabolic landscape of tumors is not currently incorporated into tumor diagnostic categories. Here we describe a set of recent discoveries on metabolic reprogramming driven by mutations in the genes for the isocitrate dehydrogenase (IDH) and receptor tyrosine kinase (RTK) pathways, which are the most commonly observed aberrations in diffuse gliomas. We highlight the importance of oncometabolites to dynamically shift the epigenetic landscape in IDH-mutant gliomas, and c-Myc and mechanistic target of rapamycin (mTOR) complexes in RTK-mutated gliomas to adapt to the microenvironment through metabolic reprogramming. These signify the integration of the genetic mutations with metabolic reprogramming and epigenetic shifts in diffuse gliomas, shedding new light onto potential patient subsets, coupled with information to guide the development of new therapeutic opportunities against the deadly types of brain tumors.
Iqbal J, Amador C, McKeithan TW, Chan WCMolecular and Genomic Landscape of Peripheral T-Cell Lymphoma.
Cancer Treat Res. 2019; 176:31-68 [PubMed
] Related Publications
Peripheral T-cell lymphoma (PTCL) is an uncommon group of lymphoma covering a diverse spectrum of entities. Little was known regarding the molecular and genomic landscapes of these diseases until recently but the knowledge is still quite spotty with many rarer types of PTCL remain largely unexplored. In this chapter, the recent findings from gene expression profiling (GEP) studies, including profiling data on microRNA, where available, will be presented with emphasis on the implication on molecular diagnosis, prognostication, and the identification of new entities (PTCL-GATA3 and PTCL-TBX21) in the PTCL-NOS group. Recent studies using next-generation sequencing have unraveled the mutational landscape in a number of PTCL entities leading to a marked improvement in the understanding of their pathogenesis and biology. While many mutations are shared among PTCL entities, the frequency varies and certain mutations are quite unique to a specific entity. For example, TET2 is often mutated but this is particularly frequent (70-80%) in angioimmunoblastic T-cell lymphoma (AITL) and IDH2 R172 mutations appear to be unique for AITL. In general, chromatin modifiers and molecular components in the CD28/T-cell receptor signaling pathways are frequently mutated. The major findings will be summarized in this chapter correlating with GEP data and clinical features where appropriate. The mutational landscape of cutaneous T-cell lymphoma, specifically on mycosis fungoides and Sezary syndrome, will also be discussed.
Baumhoer D, Amary F, Flanagan AMAn update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing.
Genes Chromosomes Cancer. 2019; 58(2):88-99 [PubMed
] Related Publications
The last decade has seen the majority of primary bone tumor subtypes become defined by molecular genetic alteration. Examples include giant cell tumour of bone (H3F3A p.G34W), chondroblastoma (H3F3B p.K36M), mesenchymal chondrosarcoma (HEY1-NCOA2), chondromyxoid fibroma (GRM1 rearrangements), aneurysmal bone cyst (USP6 rearrangements), osteoblastoma/osteoid osteoma (FOS/FOSB rearrangements), and synovial chondromatosis (FN1-ACVR2A and ACVR2A-FN1). All such alterations are mutually exclusive. Many of these have been translated into clinical service using immunohistochemistry or FISH. 60% of central chondrosarcoma is characterised by either isocitrate dehydrogenase (IDH) 1 or IDH2 mutations distinguishing them from other cartilaginous tumours. In contrast, recurrent alterations which are clinically helpful have not been found in high grade osteosarcoma. High throughput next generation sequencing has also proved valuable in identifying germ line alterations in a significant proportion of young patients with primary malignant bone tumors. These findings will play an increasing role in reaching a diagnosis and in patient management.
BACKGROUND: Glioblastoma multiform (GBM) is a devastating brain tumor with maximum surgical resection, radiotherapy plus concomitant and adjuvant temozolomide (TMZ) as the standard treatment. Diverse clinicopathological and molecular features are major obstacles to accurate predict survival and evaluate the efficacy of chemotherapy or radiotherapy. Reliable prognostic biomarkers are urgently needed for postoperative GBM patients.
METHODS: The protein coding genes (PCGs) and long non-coding RNA (lncRNA) gene expression profiles of 233 GBM postoperative patients were obtained from The Cancer Genome Atlas (TCGA), TANRIC and Gene Expression Omnibus (GEO) database. We randomly divided the TCGA set into a training (n = 76) and a test set (n = 77) and used GSE7696 (n = 80) as an independent validation set. Survival analysis and the random survival forest algorithm were performed to screen survival associated signature.
RESULTS: Six PCGs (EIF2AK3, EPRS, GALE, GUCY2C, MTHFD2, RNF212) and five lncRNAs (CTD-2140B24.6, LINC02015, AC068888.1, CERNA1, LINC00618) were screened out by a risk score model and formed a PCG-lncRNA signature for its predictive power was strongest (AUC = 0.78 in the training dataset). The PCG-lncRNA signature could divide patients into high- risk or low-risk group with significantly different survival (median 7.47 vs. 18.27 months, log-rank test P < 0.001) in the training dataset. Similar result was observed in the test dataset (median 11.40 vs. 16.80 months, log-rank test P = 0.001) and the independent set (median 8.93 vs. 16.22 months, log-rank test P = 0.007). Multivariable Cox regression analysis verified that it was an independent prognostic factor for the postsurgical patients with GBM. Compared with IDH mutation status, O-(6)-methylguanine DNA methyltransferase promoter methylation status and age, the signature was proved to have a superior predictive power. And stratified analysis found that the signature could further separated postoperative GBM patients who received TMZ-chemoradiation into high- and low-risk groups in TCGA and GEO dataset.
CONCLUSIONS: The PCG-lncRNA signature was a novel prognostic marker to predict survival and TMZ-chemoradiation response in GBM patients after surgery.
We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases. In three of the ten cases, single cell analysis of enriched CD34
Miyake K, Baba Y, Ishimoto T, et al.Isocitrate dehydrogenase gene mutations and 2-hydroxyglutarate accumulation in esophageal squamous cell carcinoma.
Med Oncol. 2018; 36(1):11 [PubMed
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Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in overproduction of an oncometabolite, 2-hydroxyglutarate (2HG). 2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Given that IDH1 and IDH2 are attracting attention as promising therapeutic targets, better evaluation of the incidence of IDH1 and IDH2 mutations and 2HG level in human cancers is clinically important. This is the first study to assess their incidence in esophageal squamous cell carcinomas (ESCCs). First, we established pyrosequencing assays for IDH1 and IDH2 mutations and revealed that these mutations were absent in 10 ESCC cell lines and 96 ESCC tissues. Second, utilizing IDH1 and IDH2 overexpression vectors, we demonstrated that LC-MS/MS assays can accurately evaluate 2HG level and found that some ESCC cases presented a high level of 2HG. In conclusion, IDH1 or IDH2 mutations play a limited role in the development of ESCC. 2HG is potentially synthesized to high levels in the absence of IDH1 and IDH2 mutations, and this may correlate with progression of ESCCs.
Seok J, Yoon SH, Lee SH, et al.The oncometabolite d‑2‑hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway.
Int J Oncol. 2019; 54(2):753-763 [PubMed
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The mutation of isocitrate dehydrogenase (IDH)1 (R132H) and IDH2 (R172K) and the induction of hypoxia in various solid tumors results in alterations in metabolic profiles, including the production of the d‑ or l‑forms of 2‑hydroxyglutarate (2HG) from α‑ketoglutarate in aerobic metabolism in the tricarboxylic acid (TCA) cycle. However, it is unclear whether the oncometabolite d‑2HG increases angiogenesis in endothelial cells. Therefore, in this study, we analyzed the levels of various metabolites, including d‑2HG, under hypoxic conditions and in IDH2R172K mutant breast cancer cells by mass spectrometry. We then further evaluated the effects of this metabolite on angiogenesis in breast cancer cells. The results revealed that treatment with d‑2HG increased the levels of secreted vascular endothelial growth factor (VEGF) in cancer cells and enhanced endothelial cell proliferation in a concentration‑dependent manner. Wound healing and cell migration (examined by Transwell assay) were significantly increased by d‑2HG to a level similar to that induced by VEGF. Tube formation was significantly stimulated by d‑2HG, and chick chorioallantoic membrane angiogenesis was also enhanced by d‑2HG. d‑2HG activated VEGF receptor (VEGFR)2 and VEGFR2 downstream signaling, extracellular signal‑regulated kinase 1/2, focal adhesion kinase, AKT and matrix metalloproteinase (MMP)2. Taken together, the findings of this study suggested that d‑2HG induced angiogenic activity via VEGFR2 signaling and increased MMP2 activity.
Bejar RWhat biologic factors predict for transformation to AML?
Best Pract Res Clin Haematol. 2018; 31(4):341-345 [PubMed
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Transformation of myelodysplastic syndromes (MDS) into secondary acute myeloid leukemia (sAML) is defined by an arbitrary boundary of ≥20% bone marrow blasts but does not necessarily reflect a defined biological transition. The more obvious distinction lies between MDS patients that have an isolated bone marrow failure phenotype and those with excess blasts. Subtyping of MDS might be more accurately stratified into clonal cytopenias and oligoblastic leukemias, using the degree of dysplasia and blast percentage as risk features, respectively, rather than as diagnostic criteria. Transformation from MDS to sAML often involves clonal evolution or expansion of existing subclones that can be assessed by changes in variant allele frequencies of the somatic mutations that define them. There are a number of predictors for transformation that have been identified: these include mutations of genes in growth signaling pathways (NRAS, KRAS, PTPN11, FLT3), mutations in genes more commonly observed in AML (NPM1, WT1, IDH2), certain cytogenetic abnormalities (monosomy 7, complex karyotype, loss of 17p). Gene expression profiles that divide MDS into two major categories identify a progenitor gene signature subtype associated with a high risk of AML transformation. Assessing for these genetic abnormalities may better identify MDS patients at greatest risk of transformation.
Liu Z, Che P, Mercado JJ, et al.Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis.
J Neurooncol. 2019; 141(2):289-301 [PubMed
] Article available free on PMC
after 01/01/2020 Related Publications
INTRODUCTION: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis.
METHODS: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH).
RESULTS: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells.
CONCLUSIONS: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.
Bergaggio E, Riganti C, Garaffo G, et al.IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies.
Blood. 2019; 133(2):156-167 [PubMed
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Proteasome inhibitors (PI) are extensively used for the therapy of multiple myeloma (MM) and mantle cell lymphoma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PI, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (
Villa C, Miquel C, Mosses D, et al.The 2016 World Health Organization classification of tumours of the central nervous system.
Presse Med. 2018 Nov - Dec; 47(11-12 Pt 2):e187-e200 [PubMed
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The 2016 WHO classification of tumours of the central nervous system represents the new paradigm among the specialists in the brain tumours and proposes a new approach combining histopathological and molecular features into diagnosis named 'integrated diagnosis'. The aim of this challenge is to overstep the interobserver variability of diagnosis based on previous classifications in order to ensure homogenous biological entities with a more accurate clinical significance. Over the last two decades, several molecular aberrations into gliomagenesis were highlighted and then confirmed as emerging biomarkers through prognostic stratification. In particular, IDH1/IDH2 genes mutations, 1p/19q codeletion and mutations in genes encoding histone H3 variants drastically changed the knowledge about diffuse gliomas inducing the WHO working group to consider the phenotype-genotype approach. In the present review, the historical development of the diagnosis of brain tumours from the 3D spatial configuration to the integration of multidisciplinary data up to recent molecular alterations is discussed. At the national level, the RENOCLIP network (supported by the National Cancer Institute) contributes to improve the standardization of histological diagnosis and the facilitation of access to molecular biology platforms for the detection of genetic aberrations necessary for integrated diagnosis. Importantly, the French POLA cohort allowed to test the clinical impact of the new criteria introduced by 2016 WHO classification of CNS tumours confirming the high accuracy in predicting clinical behaviour for diffuse gliomas.
Zhao J, Wang YL, Li XB, et al.Comparative analysis of the diffusion kurtosis imaging and diffusion tensor imaging in grading gliomas, predicting tumour cell proliferation and IDH-1 gene mutation status.
J Neurooncol. 2019; 141(1):195-203 [PubMed
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INTRODUCTION: Few studies have applied diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) for the comprehensive assessment of gliomas [tumour grade, isocitrate dehydrogenase-1 (IDH-1) mutation status and tumour proliferation rate (Ki-67)]. This study describes the efficacy of DKI and DTI to comprehensively evaluate gliomas, compares their results.
METHODS: Fifty-two patients (18 females; median age, 47.5 years) with pathologically proved gliomas were prospectively included. All cases underwent DKI examination. DKI (mean kurtosis: MK, axial kurtosis: Ka, radial kurtosis: Kr) and DTI (mean diffusivity: MD, fractional anisotropy: FA) maps of each metric was derived. Three ROIs were manually drawn.
RESULTS: MK, Ka, Kr and FA were significantly higher in HGGs than in LGGs, whereas MD was significantly lower in HGGs than in LGGs (P < 0.01). ROC analysis demonstrated that MK (specificity: 100% sensitivity: 79%) and Ka (specificity: 96% sensitivity: 82%) had the same and highest (AUC: 0.93) diagnostic value. Moreover, MK, Ka, and Kr were significantly higher in grade III than II gliomas (P ≦ 0.01). Further, DKI and DTI can significantly identify IDH-1 mutation status (P ≦ 0.03). Ka (sensitivity: 74%, specificity: 75%, AUC: 0.72) showed the highest diagnostic value. In addition, DKI metrics and MD showed significant correlations with Ki-67 (P ≦ 0.01) and Ka had the highest correlation coefficient (r
CONCLUSIONS: Compared with DTI, DKI has great advantages for the comprehensive assessment of gliomas. Ka might serve as a promising imaging index in predicting glioma grading, tumour cell proliferation rate and IDH-1 gene mutation status.
Patil V, Mahalingam KComprehensive analysis of Reverse Phase Protein Array data reveals characteristic unique proteomic signatures for glioblastoma subtypes.
Gene. 2019; 685:85-95 [PubMed
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The most common and lethal type of intracranial tumors include the astrocytomas. Grade IV astrocytoma or Glioblastoma (GBM) is highly aggressive and treatment-refractory with a median survival of only 14 to 16 months. Molecular profiling of GBMs reveals a high degree of intra- and inter-tumoral heterogeneity, and hence it is important to understand the important signalling axes that get deregulated in different GBM subtypes to provide effective tailor-made therapies. In this study, we have carried out extensive analysis of Reverse Phase Protein Array (RPPA) data from TCGA cohort to develop protein signatures that define glioma grades or subtypes. The protein signatures that distinguished Grade II or III from GBM had largely overlapped, and pathway analysis revealed the positive enrichment of extracellular matrix proteins (ECM), MYC pathway, uPAR pathway and G2/M checkpoint genes in GBM. We also identified protein signatures for GBMs with genetic alterations (IDH mutation, p53 mutation, EGFR amplification or mutation, CDKN2A/CDKN2B deletion, and PTEN mutation) that occur at high frequency. G-CIMP positive GBM-specific protein signature showed a large similarity with IDH1-mutant protein signature, thus signifying the importance of IDH1 mutation driving the G-CIMP. Gene expression subtype analysis revealed an association of specific proteins to classical (EGFR and phosphor variants), mesenchymal (SERPINE1, TAZ, and Myosin-IIa_pS1943), neural (TUBA1B), and proneural (GSK3_pS9) types. Univariate Cox regression analysis identified several proteins showing significant correlation with GBM survival. Multivariate analysis revealed that IGFBP2 and RICTOR_pT1135 are independent predictors of survival. Overall, our analyses reveal that specific proteins are regulated in different glioma subtypes underscoring the importance of diverse signalling axes playing important role in the pathogenesis of glioma tumors.