scholarly journals Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Rémy Nicolle ◽  
Mira Ayadi ◽  
Anne Gomez-Brouchet ◽  
Lucile Armenoult ◽  
Guillaume Banneau ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Tumor Differentiation ◽  
Cartilaginous Tissue ◽  
Clinical Value ◽  
Cell Cycle Activation ◽  
Recurrent Mutations ◽  
Idh Mutations ◽  
Cartilage Tumors ◽  
Molecular Profiles

Abstract Chondrosarcomas are primary cancers of cartilaginous tissue with highly contrasting prognoses. These tumors are defined by recurrent mutations in the IDH genes and other genetic alterations including inactivation of CDKN2A and COL2A1; however, these have no clinical value. Here we use multi-omics molecular profiles from a series of cartilage tumors and find an mRNA classification that identifies two subtypes of chondrosarcomas defined by a balance in tumor differentiation and cell cycle activation. The microRNA classification reveals the importance of the loss of expression of the 14q32 locus in defining the level of malignancy. Finally, DNA methylation is associated with IDH mutations. We can use the multi-omics classifications to predict outcome. We propose an mRNA-only classifier to reproduce the integrated multi-omics classification, and its application to relapsed tumor samples shows the progressive nature of the classification. Thus, it may be possible to use mRNA-based signatures to detect patients with high-risk chondrosarcomas.

Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation

2020 ◽  
Vol 20 (7) ◽  
pp. 490-500 ◽  
Author(s):  
Justin S. Becker ◽  
Amir T. Fathi
Keyword(s):  
Genome Structure ◽  
Cellular Metabolism ◽  
Standard Of Care ◽  
Competitive Inhibitor ◽  
Driver Mutations ◽  
New Class ◽  
Regulatory Enzymes ◽  
Idh Mutations ◽  
Genomic Characterization

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

scholarly journals Copy Number Variation and Rearrangements Assessment in Cancer: Comparison of Droplet Digital PCR with the Current Approaches

2021 ◽  
Vol 22 (9) ◽  
pp. 4732
Author(s):  
Vincenza Ylenia Cusenza ◽  
Alessandra Bisagni ◽  
Monia Rinaldini ◽  
Chiara Cattani ◽  
Raffaele Frazzi
Keyword(s):  
Digital Pcr ◽  
Genetic Alterations ◽  
Droplet Digital Pcr ◽  
Molecular Oncology ◽  
Therapeutic Choice ◽  
Golden Standard ◽  
Number Variation ◽  
Key Aspects

The cytogenetic and molecular assessment of deletions, amplifications and rearrangements are key aspects in the diagnosis and therapy of cancer. Not only the initial evaluation and classification of the disease, but also the follow-up of the tumor rely on these laboratory approaches. The therapeutic choice can be guided by the results of the laboratory testing. Genetic deletions and/or amplifications directly affect the susceptibility or the resistance to specific therapies. In an era of personalized medicine, the correct and reliable molecular characterization of the disease, also during the therapeutic path, acquires a pivotal role. Molecular assays like multiplex ligation-dependent probe amplification and droplet digital PCR represent exceptional tools for a sensitive and reliable detection of genetic alterations and deserve a role in molecular oncology. In this manuscript we provide a technical comparison of these two approaches with the golden standard represented by fluorescence in situ hybridization. We also describe some relevant targets currently evaluated with these techniques in solid and hematologic tumors.

scholarly journals Graphene, an Interesting Nanocarbon Allotrope for Biosensing Applications: Advances, Insights, and Prospects

2021 ◽  
Vol 12 ◽  
pp. 117959722098382
Author(s):  
Farid Menaa ◽  
Yazdian Fatemeh ◽  
Sandeep K Vashist ◽  
Haroon Iqbal ◽  
Olga N Sharts ◽  
...  
Keyword(s):  
Cost Effective ◽  
Genetic Alterations ◽  
Multiplex Detection ◽  
Quantitative Characterization ◽  
Disease Biomarkers ◽  
Qualitative And Quantitative ◽  
Sensing Systems ◽  
Doped Graphene ◽  
Bioanalytical Applications

Graphene, a relatively new two-dimensional (2D) nanomaterial, possesses unique structure (e.g. lighter, harder, and more flexible than steel) and tunable physicochemical (e.g. electronical, optical) properties with potentially wide eco-friendly and cost-effective usage in biosensing. Furthermore, graphene-related nanomaterials (e.g. graphene oxide, doped graphene, carbon nanotubes) have inculcated tremendous interest among scientists and industrials for the development of innovative biosensing platforms, such as arrays, sequencers and other nanooptical/biophotonic sensing systems (e.g. FET, FRET, CRET, GERS). Indeed, combinatorial functionalization approaches are constantly improving the overall properties of graphene, such as its sensitivity, stability, specificity, selectivity, and response for potential bioanalytical applications. These include real-time multiplex detection, tracking, qualitative, and quantitative characterization of molecules (i.e. analytes [H2O2, urea, nitrite, ATP or NADH]; ions [Hg2+, Pb2+, or Cu2+]; biomolecules (DNA, iRNA, peptides, proteins, vitamins or glucose; disease biomarkers such as genetic alterations in BRCA1, p53) and cells (cancer cells, stem cells, bacteria, or viruses). However, there is still a paucity of comparative reports that critically evaluate the relative toxicity of carbon nanoallotropes in humans. This manuscript comprehensively reviews the biosensing applications of graphene and its derivatives (i.e. GO and rGO). Prospects and challenges are also introduced.

16. Physiological effects of IDH1 loss-of-function on Chondrocyte Differentiation through Hedgehog Pathway upregulation

2018 ◽  
Author(s):  
Cassie Tyson
Keyword(s):  
Developmental Stages ◽  
Hedgehog Pathway ◽  
Chondrocyte Differentiation ◽  
Loss Of Function ◽  
Wild Type ◽  
Phenotypic Analysis ◽  
Growth Plate Chondrocytes ◽  
Idh Mutations ◽  
Cartilage Tumors ◽  
Deficient Mice

Cartilage tumors are the most common and terminal primary neoplasms in bone. Physiologically, bones formed through endochondral ossification are regulated by the Hedgehog pathway and Parathyroid hormone-like hormone feedback loop. The upregulation of the infamous Hedgehog pathway has been demonstrated in several non-cartilaginous neoplasms. Recently, frequent mutational events of isocitrate dehydrogenase1 (IDH1) were identified in cartilage tumors. In other neoplasms, IDH mutations produces an oncometabolite that can promote HIF1a activation, contributing to tumorigenesis. Currently, the role of IDH1 mutations in cartilage tumors remain unknown. Investigating the physiological aspect of IDH1proves useful in identifying novel therapeutic targets for cartilage tumors. IDH1 deficient and wild-type littermates, were harvested for forelimbs and hindlimbs at various developmental stages for phenotypic analysis via hematoxylin and eosin staining. Histological analysis demonstrated IDH1 homozygous deficient mice at embryonic stages exhibited dwarfism and an elongated layer of hypertrophic chondrocytes. This was verified via immunohistochemistry Type 10 Collagen staining and Quantitative PCR (qPCR) using the chondrocyte terminal differentiation marker Col10a1. Whole skeletons of IDH1 deficient mice were subjected to skeletal double staining which demonstrated delayed mineralization of underdeveloped IDH1 deficient mice contrasted with wild-type littermates. qPCR was performed to examine the status of chondrocyte differentiation through the Hedgehog pathway in cultured primarymouse growth plate chondrocytes. Interestingly, IDH1 deficient non-neoplastic cells revealed significant upregulation of Hedgehog target molecules in IDH1 deficient chondrocytes. As a result, the loss-offunction of IDH1 was identified as a potential impairment of chondrocyte differentiation and a factor towards chondrocyte tumorgenisis.

scholarly journals From genomics to the clinic: biological and translational insights of mutant IDH1/2 in glioma

2013 ◽  
Vol 34 (2) ◽  
pp. E2 ◽  
Author(s):  
Gavin P. Dunn ◽  
Ovidiu C. Andronesi ◽  
Daniel P. Cahill
Keyword(s):  
Hypoxia Inducible Factor ◽  
Diagnostic Tools ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Treatment Algorithms ◽  
Recurrent Mutations ◽  
Molecular Landscape ◽  
Mutant Idh1 ◽  
And Function

The characterization of the genomic alterations across all human cancers is changing the way that malignant disease is defined and treated. This paradigm is extending to glioma, where the discovery of recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) gene has shed new light on the molecular landscape in glioma and other IDH-mutant cancers. The IDH1 mutations are present in the vast majority of low-grade gliomas and secondary glioblastomas. Rapidly emerging work on the consequences of mutant IDH1 protein expression suggests that its neomorphic enzymatic activity catalyzing the production of the oncometabolite 2-hydroxyglutarate influences a range of cellular programs that affect the epigenome, transcriptional programs, hypoxia-inducible factor biology, and development. In the brief time since its discovery, knowledge of the IDH mutation status has had significant translational implications, and diagnostic tools are being used to monitor its expression and function. The concept of IDH1-mutant versus IDH1-wild type will become a critical early distinction in diagnostic and treatment algorithms.

scholarly journals Clinical-Pathological, Immunohistochemical, and Genetic Characterization of a Series of Posterior Pituitary Tumors

2020 ◽  
Vol 80 (1) ◽  
pp. 45-51
Author(s):  
Valeria Barresi ◽  
Michele Simbolo ◽  
Marco Gessi ◽  
Sabrina Rossi ◽  
Maria Caffo ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Pituitary Tumors ◽  
Granular Cell ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Posterior Pituitary ◽  
Chromosome 1P ◽  
Genetic Features ◽  
Older Subjects

Abstract Posterior pituitary tumors are supposed to represent the morphological spectrum of a single entity. Herein, we report the clinical-pathological, immunohistochemical, and genetic features of 5 spindle cell oncocytomas (SCOs), 3 pituicytomas, and 1 granular cell tumor (GCT). SCOs had the highest local invasiveness and affected older subjects. The 3 histotypes differed in the content of spindle cells (predominant in pituicytoma and absent in GCT), presence of lymphocytic infiltrate (in SCO and GCT, but not in the pituicytoma) and EMA/GFAP staining (negative in GCT; EMA-positive/GFAP-negative in 4/5 SCO and GFAP-positive in 3/3 pituicytomas). Three SCOs and 1 pituicytoma analyzed with next-generation sequencing had no mutations in 409 genes. However, 1 SCO had previously unreported homozygous deletion of CDKN2A/B and another of SMARCA4, SMARCB1, and NF2. All 3 SCOs had loss of heterozygosity of chromosome 1p, while the pituicytoma had chromosome 19 homozygous loss and chromosomes 10, 13q, and 18q loss of heterozygosity. Since 1p and 13q losses were previously reported in 1 pituicytoma and 1 SCO, respectively, our data demonstrate that posterior pituitary tumors share common genetic alterations. The possibility that posterior pituitary tumors are SMARCA4/SMARCB1-deficient should be kept in mind in the differential diagnosis toward other entities.

scholarly journals OS1.4 Liquid biopsy of the CSF in a series of GBM patients: preliminary results

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii6-iii6
Author(s):  
R Rudà ◽  
F Bruno ◽  
F De Bacco ◽  
F Orzan ◽  
P Cassoni ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Point Mutations ◽  
Digital Pcr ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Molecular Profile ◽  
Genetic Profile ◽  
Radiological Features ◽  
Meningeal Involvement ◽  
Idh Mutations

Abstract BACKGROUND Liquid biopsy (LB) by cerebrospinal fluid (CSF) can be useful to identify circulating tumour DNA (ctDNA), thus offering information about the heterogeneity of the neoplastic genome. The aim of our study is to assess the effectiveness of LB of the CSF in detecting ctDNA which mirrors the genetic profile of the tumoural tissue, and to investigate the clinical and radiological aspects influencing the availability of ctDNA. MATERIAL AND METHODS Tumoral tissue and CSF samples of 13 GBM patients undergoing surgery was collected. CSF was withdrawn from the very proximity of the tumoural surface before the excision. DNA extracted from tissue samples was analysed by qPCR to identify typical genetic alterations such as copy number variations (EGFR, PDGFRA, CDK4, MDM2, CDKN2A), and point mutations (TP53, PTEN, IDH, NRAS, PI3K1, pTERT). CtDNA extracted from CSF was analysed by droplet digital PCR to assess the presence of the alterations found in the matching tissue. Both contrast-enhanced (CE) and FLAIR volumes of the lesions were measured in the pre-surgical MRI. Linear and logarithmic regressions were employed for the statistical analysis. RESULTS From June 2016 to February 2017 we prospectively collected 13 GBM patients. Median age was 73 years. All lesions showed CE at the MRI; other radiological findings included necrosis (84.6%), oedema (76.9%), cortical, ventricular or meningeal involvement (76.9%, 30.8%, and 15.4%). Median volumes of CE and FLAIR lesions were 28.6 and 25.5 cm3, with a median FLAIR/CE ratio of 72.9. Surgery was subtotal (<95%) in all patients. All GBM tissues were tested for the following alterations: EGFR, PDGFRA, CDK4, MDM2, CDKN2A; 76.9% were tested for TP53, PTEN, and IDH mutations; 38.5% for NRAS and pTERT mutations; 30.8% for PI3KR1 mutation. MGMT methylation was assessed in 12 cases (92.3%) and found in 7 (58.3%). Median CSF volume, ctDNA quantity and concentration were 0.45 mL, 59.64 ng, and 0.42 ng/μL. Processable DNA was found in 11 CSF specimens (84.6%), in 8 of which (61.5%) it carried the same alteration expressed by the tumoural cells of the matched tissue, while in 3 cases (23.1%) it seemed to have a different genetic profile; finally, in 2 cases it was not possible to detect any circulating DNA in the CSF. Preliminary data on 13 patients suggest that the ctDNA concentration in the CSF could be related to the FLAIR/CE ratio as measured in the MRI before surgery (p = 0.02). Other correlations between the molecular and the radiological features are still being exploring. CONCLUSION Our study confirms that LB of CSF can detect ctDNA carrying the same molecular profile harboured in the tumour. Therefore, it seems to be an accurate method to identify markers useful for the diagnosis and the monitoring of the disease. Additionally, our ongoing study is trying to demonstrate a potential correlation between radiological features of the tumour and availability of ctDNA in CSF.

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