Ales Vicha
Charles University, Prague, Pediatric Hematology and Oncology, Faculty Member
Pontine gliomas represent difficult to treat entity due to the location and heterogeneous biology varying from indolent low-grade gliomas to aggressive diffuse intrinsic pontine glioma (DIPG). Making the correct tumor diagnosis in the... more
Pontine gliomas represent difficult to treat entity due to the location and heterogeneous biology varying from indolent low-grade gliomas to aggressive diffuse intrinsic pontine glioma (DIPG). Making the correct tumor diagnosis in the pontine location is thus critical. Here, we report a case study of a 14-month-old patient initially diagnosed as histone H3 wild-type DIPG. Due to the low age of the patient, the MRI appearance of DIPG, and anaplastic astrocytoma histology, intensive chemotherapy based on the HIT-SKK protocol with vinblastine maintenance chemotherapy was administered. Rapid clinical improvement and radiological regression of the tumor were observed with nearly complete remission with durable effect and excellent clinical condition more than 6.5 years after diagnosis. Based on this unexpected therapeutic outcome, genome-wide DNA methylation array was employed and the sample was classified into the methylation class “Low-grade glioma, MYB(L1) altered.” Additionally, RT-P...
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The current progress and increasing knowledge about the genetic causes of cancer opens up new possibilities for its treatment. However, it is necessary to combine the results obtained using classical pathological methods with sensitive,... more
The current progress and increasing knowledge about the genetic causes of cancer opens up new possibilities for its treatment. However, it is necessary to combine the results obtained using classical pathological methods with sensitive, multiplex molecular pathological methods. The method that meets the required criteria is MLPA based on multiplex PCR reaction. This method detects both changes in gene copy number and DNA methylation and, last but not least, point mutations. The MLPA reaction is applicable to even highly fragmented DNA. At the same time, it is a robust method that can be performed on standard thermocyclers, the fluorescent tip label requires automatic sequencers. Up to 50 genetic markers can be tested in one reaction, a number that allows a diagnostic and prognostic conclusion. All these features lead to the routine use of MLPA analysis not only in diagnosis but also in cancer research. The present article aims to summarize the different types of MLPA reactions, its benefits, but also the potential pitfalls.
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The new WHO classification of CNS tumors is largely based on molecular diagnostic. Without molecular methods some entities can no longer be diagnosed. We are trying to show a rational approach to the CNS tumors diagnostics, which is based... more
The new WHO classification of CNS tumors is largely based on molecular diagnostic. Without molecular methods some entities can no longer be diagnosed. We are trying to show a rational approach to the CNS tumors diagnostics, which is based on conventional molecular methods such as RT-PCR, Sanger sequencing, MLPA, extended by the next generation sequencing (NGS) and methylation SNP array.
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1 Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic 2 Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine,... more
1 Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic 2 Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol in Prague, Czech Republic 3 Department of Oncology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic 4 Institute of Pathology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic 5 Institute of Endocrinology, Prague, Czech Republic 6 Department of Nephrology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic 7 Department of Paediatrics of the 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol in Prague, Czech Republic *Coressponding Author’s E-mail: musil.z@seznam.cz Tel.: +420-224968164; Fax.: +420224918666 Renal anomalies are quite a common medical condition thought to be genetically influenced. The subject of this work was to conduct molecular genetic analysis of two human renal agenesis causing candidate genes encoding the RET receptor thyrosin kinase and GDNF neutrophic factor. The mutational analysis of twenty RET exons and three GDNF exons in twenty patients diagnosed with unilateral renal agenesis was carried out. Furthermore, copy number changes in both genes were investigated. The aim of this work was to identify potential mutations of RET/GDNF genes and thus to prove their association with renal agenesis. In this group of patients, no known pathogenic mutations were discovered, only three known single nucleotide polymorphisms of the RET gene were detected. Polymorphism rs1800860 (GCG-GCA, Ala432) was detected in 11/20 patients, two of them in a homozygous state. Polymorphism rs1800861 (CTT-CTG, Leu769) was identified in 6/20 patients, where one patient was a homozygote for the minor allele G. Polymorphism rs1800863 (TCC-TCG, Ser904) was detected in 5/20 patients, always in heterozygous combinations. All these polymorphisms are common ones with the minor allele frequency in population higher than 10%. Results of this study did not confirm an increased incidence of RET and GDNF mutations in patients diagnosed with renal agenesis and thus the association of these genes with renal agenesis cannot be proved. Nevertheless, with regard to a limited size of the patient group, the association between RET/GDNF signal complex and renal agenesis cannot be excluded. Submitted paper is a pilot study of patients with CAKUT in the Czech Republic, we intend to continue collecting samples and examine more genes relating to these anomalies.
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To the Editor: Lipoblastomas are rare, benign adipose tissue tumors that occur primarily in infants and children below 3 years of age. Although lipoblastomas are usually localized and well-circumscribed tumors, part of them can have... more
To the Editor: Lipoblastomas are rare, benign adipose tissue tumors that occur primarily in infants and children below 3 years of age. Although lipoblastomas are usually localized and well-circumscribed tumors, part of them can have diffuse infiltrative growth patterns known as lipoblastomatosis. Lipoblastomatosis has a higher risk of recurrence than ordinary lipoblastoma. Histologically, lipoblastomas are composed of an admixture of mature adipocytes and lipoblasts at various stages of development.1 Lipoblastomas are characterized by chromosome rearrangement of chromosomearm8p,which occurs in about 70%of cases. Rearrangements concern the pleomorphic adenoma gene 1 (PLAG1).2,3 The 8q12 rearrangements in lipoblastoma are associated with promoter swapping, in which the PLAG1 promoter is replaced by an active promoter from the other gene, for exampleHAS2 (hyaluronic acid synthase 2) or COL1A2 (collagen 1 α 2),4,5 COL3A1 (collagen 3 α 1), or in single case RAB2A (Ras-related protein)4 or BOC (BOC cell adhesion associated, oncogene regulated).6 The promoter swapping mechanism results in overexpression of a normal PLAG1 protein. In contrast, PLAG1 rearrangement is uncommon in other types of adipose tumors, including lipoma and liposarcoma. We examined whether our lipomatous tumors had one of the two most common fusion genes, HAS2-PLAG1 and COL1A2-PLAG1 (Table S1). Due to RNA degradation and impossibility to amplify longer PCR products from FFPE material, next-generation sequencing using Sarcoma FusionPlex panel (Archer) was performed to identify molecular alteration of PLAG1 gene in Case 1. We identified a novel, yet undescribed ZEB2-PLAG1 fusion gene. Exon 1 of ZEB2 fused to exon 2 (Figure 1) ofPLAG1 and exon1ofZEB2 to exon 3ofPLAG1 (Supplemental Figure S1). The two fusion transcripts are the result fromalternative splicing. HAS2-PLAG1 fusion gene was found in one lipoma and two lipoblastomas. In all three cases, we identified two fusion transcripts (HAS2 ex1-PLAG1 ex3 and HAS2 ex1-PLAG1 ex2) resulting from alternative splicing. COL1A2-PLAG1 fusion was detected in one lipoblastoma. In one case, we identified fusion gene RAB2A-PLAG1 (Supplemental Figure S2) using primers described by Yoshida et al.4 In this case, we found hyper rearrangement in the chromosome 8 (Supplemental Figure S3) using single nucleotide polymorphismmicroarray. We describe four different PLAG1 gene fusion partners in five patients with lipoblastoma and in one lipoma. PLAG1 is an oncogene that was first observed in pleomorphic adenoma of salivary glands.4,5 This gene encodes a zinc finger protein. Its oncogenicity is partly because of activation of the insulin-like growth factor 2 (IGF2) mitogenic pathway.4,7 The entire PLAG1 coding sequence, which begins in the exon 4, is placed under the transcriptional control of an active promoter region of its fusion partner. The PLAG1 rearrangement results in promoter swapping, in which PLAG1 promoter is replaced by promoter region from another gene as: HAS2 at 8q24.1, COL1A2 at 7q22, COL3A1 at 2q31 or RAB2A at 8q12.1. We found a novel fusion gene ZEB2-PLAG1. ZEB2 (Zinc Finger E-Box Binding Homeobox 2) in 2q22.3 is the gene encoding protein, which is a member of the Zfh1 family of two-handed zinc finger/homeodomain proteins. It is located in the nucleus and functions as a DNA-binding transcriptional repressor that interacts with activated SMADs, the transducers of TGF-beta signaling, and interacts with the nucleosome remodeling and histone deacetylation complex.8 Sequence analysis of ZEB2-PLAG1 fusion gene showed that the exon 1 of ZEB2 fused to the exon 2 or 3 of PLAG1. We are of the opinion that placing all functional domains of PLAG1 under control of ZEB2 promoter represents the oncogenic mechanism for the ZEB2-PLAG1 fusion gene, similar to other PLAG1 fusion partners. PLAG1 overexpression in lipoblastoma with PLAG1 rearrangement is postulated to be result of a promoter swapping event.5,6 From our quantitative expression analysis (Supplemental Figure S4), it is apparent that high expression of the PLAG1 gene is a common feature of all PLAG1 fusion rearrangements.
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Ewing family of tumors is a group of highly aggressive neoplasias that occur most commonly in the first two decades of life. These tumors are most frequently localized in bones, less frequently in soft tissues. They usually appear as... more
Ewing family of tumors is a group of highly aggressive neoplasias that occur most commonly in the first two decades of life. These tumors are most frequently localized in bones, less frequently in soft tissues. They usually appear as undifferentiated small round-cell tumors. With current treatment regiments, 5-year disease-free survival rates exceed 60% in patients with a localized disease. Patients
Research Interests: Pathology, Molecular Biology, Biology, Immunohistochemistry, Medicine, and 14 moreCytogenetics, Cancer Genetics, Humans, Child, Female, Karyotyping, Bone marrow, Immunochemistry, Soft Tissue, MINIMAL RESIDUAL DISEASE, Bone Marrow Cells, Chromosome Banding, reverse transcriptase polymerase chain reaction, and Disease Free Survival
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Rezistence nadorových buněk k cytostatikům je způsobena řadou mechanismů, ktere se casto kombinuji. Bylo popsano, že vysoka koncentrace thiolových skupin v cytoplazmě važe platinove alkylacni derivaty a chemorezistence je způsobena... more
Rezistence nadorových buněk k cytostatikům je způsobena řadou mechanismů, ktere se casto kombinuji. Bylo popsano, že vysoka koncentrace thiolových skupin v cytoplazmě važe platinove alkylacni derivaty a chemorezistence je způsobena přenosem platiny z cytostatika na MT, ktere je inaktivuji. Protože jsme v nasich předchozich studiich prokazali zvýseni hladin MT v rezistentnich neuroblastomových /NB/ liniich, ale ne v senzitivnich liniich po inkubaci s platinovými cytostatiky zabývali jsme se významem MT-3 pro buňky NB. Metoda: Buňky NB linie SiMa transfekovane vektorem obsahujicim lidský MT-3 a GFP nebo pouze GFP (kontrola). Expresni microarray (Custom Array, Bothell, WA, USA), exprese MT-3 a nejvice exprimovaných genů validovana RT PCR. Citlivost k CDDP: MTT test, vysetřeni klonogenicity, průkaz stěpeni caspasy 3 blotem a volne kyslikove radikaly /ROS/ fluorescencni mikroskopii. Hladiny mRNA MT-3 ve 23 vzorcich vysoce rizikových NB, buňkach normalni lidske kůry nadlediny byly vysetřeny RT PCR.. Výsledky: Expresni microarray prokazala downregulaci 3 a overexpresi 19 genů u MT-3 transfekovaných NB buněk. Pomoci genove ontologie bylo zjistěno, že overexprimovane geny řidi onkogeny indukovanou senescenci ( CDKN2B a ANAPC5 ), a zvýseně exprimovane byly i geny glutathion S-transferasy M3, caspasy 4 a DNAJB6 (chaperon neuronalnich proteinů). Prokazali jsme sniženou senzitivitu MT-3 transfekovaných buněk k CDDP (24h IC 50 7,48± 0,97 a 19,81± 1,2 µg/ml), vyssi pocet kolonii po inkubaci s CDDP, snižene stěpeni caspasy 3 po inkubaci s CDDP a nižsi ROS po jejich indukci CDDP. Buňky vysoce rizikových NB exprimovaly MT-3 významně vice než nenadorove buňky nadledviny, ale nepodařilo se prokazat jednoznacný vztah k průběhu onemocněni. Zavěr: Prokazali jsme vztah mezi MT-3 a geny onkogeny indukovane senescence a některými dalsimi geny významnými pro osud buňky ( glutathion S-transferasa M3, caspasa 4 a DNAJB6 ) a významný podil MT-3 na rezistenci k CDDP. Vysoke hladiny MT-3 u vysoce rizikoveho NB by mohly být jednou z přicin castých recidiv u tohoto nadoru.
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Gliomas are the most common central nervous tumors in children and adolescents. However, spinal cord low-grade gliomas (sLGGs) are rare, with scarce information on tumor genomics and epigenomics. To define the molecular landscape of... more
Gliomas are the most common central nervous tumors in children and adolescents. However, spinal cord low-grade gliomas (sLGGs) are rare, with scarce information on tumor genomics and epigenomics. To define the molecular landscape of sLGGs, we integrated clinical data, histology, and multi-level genetic and epigenetic analyses on a consecutive cohort of 26 pediatric patients. Driver molecular alteration was found in 92% of patients (24/26). A novel variant of KIAA1549:BRAF fusion (ex10:ex9) was identified using RNA-seq in four cases. Importantly, only one-third of oncogenic drivers could be revealed using standard diagnostic methods, and two-thirds of pediatric patients with sLGGs required extensive molecular examination. The majority (23/24) of detected alterations were potentially druggable targets. Four patients in our cohort received targeted therapy with MEK or NTRK inhibitors. Three of those exhibited clinical improvement (two with trametinib, one with larotrectinib), and two p...
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INTRODUCTION: Paediatric high-grade gliomas (HGG) are characterised by the aggressive biological behaviour with dismal prognosis of long-term survival 10-15%. Current molecular-biological diagnostic approaches allow for more precise... more
INTRODUCTION: Paediatric high-grade gliomas (HGG) are characterised by the aggressive biological behaviour with dismal prognosis of long-term survival 10-15%. Current molecular-biological diagnostic approaches allow for more precise characterization and determination of new unique subgroups of HGG. Our aim was to identify novel and rare HGG subgroups within our institution cohort. PATIENTS AND METHODS: Our reference centre patients′ cohort consisted of 97 clinically annotated patients with HGG diagnosed between 2000 and 2021. Sanger sequencing was used for screening of the most common HGG-related oncogenic drivers; furthermore we employed whole genome methylation array (Illumina Infinium MethylationEPIC BeadChip) and for selected samples RNA sequencing and expression profiling. RESULTS: Based on H3 status and previous radiotherapy we separated our HGG cases into the RIG, H3mut and H3wt groups. In contrast to H3mut(n=35) and RIG(n=11) that were uniformly fatal, H3wt group contained a...
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Molecular assays for translocation detection in different tumors have gradually been incorporated into routine diagnostics. However, conventional methods such as fluorescence in situ hybridization (FISH) and reverse transcriptase-PCR come... more
Molecular assays for translocation detection in different tumors have gradually been incorporated into routine diagnostics. However, conventional methods such as fluorescence in situ hybridization (FISH) and reverse transcriptase-PCR come with several drawbacks. Next-generation sequencing (NGS) can provide in-depth detection of numerous gene alterations. The anchored multiplex PCR assay proved to be a fast and easy-to-analyze approach for routine diagnostics laboratories. Next-generation sequencing-based anchored multiplex PCR technique (Archer FusionPlex Panels) is beneficial in both diagnosis for patient care and in identification of a novel fusion breakpoint in tumors. NGS is useful in identifying targetable molecular changes (point mutations, fusion genes, etc.) in tumors that can serve as a rationale for inclusion of patients with advanced disease in ongoing clinical trials and allow for better risk stratification.
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Examination of changes in the methylation profile of DNA in cancer is currently used to determine the diagnosis or prognostic and predictive biomarkers. It complements histological or molecular biological examinations. At the same time,... more
Examination of changes in the methylation profile of DNA in cancer is currently used to determine the diagnosis or prognostic and predictive biomarkers. It complements histological or molecular biological examinations. At the same time, it helps to identify new diagnostic groups and subgroups. Currently, this diagnosis is most common in brain tumors, where it has become a routine examination. The established methylation profile may help even where the diagnosis or subgroup classification of the disease cannot be determined in any other way, as is the case with medulloblastoma.
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BACKGROUND Resistance of cancer cells to cytostatics is caused by a number of mechanisms that are often combined. These include reduced cell entry or increased efflux, increased DNA repair, defects of, apoptotic pathways, increased... more
BACKGROUND Resistance of cancer cells to cytostatics is caused by a number of mechanisms that are often combined. These include reduced cell entry or increased efflux, increased DNA repair, defects of, apoptotic pathways, increased cytostatic degradation as well as elevated levels of intracellular thiols of glutathione and metallothioneins (MT). It has been reported that high concentrations of thiol groups in the cytoplasm bind platinum alkylation derivatives and chemorezistence is due to the transfer of platinum from the cytostatic to MT, which inactivates them. Because we have shown an increase in MT levels in resistant neuroblastoma (NB) lines, but not in sensitive lines after incubation with platinum cytostatics, we have considered MT-3 for NB cells in our previous studies. METHOD SiMa NB cell lines transfected with vector containing human MT-3 and GFP or GFP only (control). Expression Microarray Human Cancer 3711 ElectraSense medium density 4 × 2k array slides with 1,609 DNA pr...
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Paediatric tumours are often characterised by the presence of recurrent DNA copy number alterations (CNAs). These DNA copy number profiles, obtained from a tissue biopsy, can aid in the correct prognostic classification and therapeutic... more
Paediatric tumours are often characterised by the presence of recurrent DNA copy number alterations (CNAs). These DNA copy number profiles, obtained from a tissue biopsy, can aid in the correct prognostic classification and therapeutic stratification of several paediatric cancer entities (e.g. MYCN amplification in neuroblastoma) and are part of the routine diagnostic practice. Liquid biopsies (LQBs) offer a potentially safer alternative for such invasive tumour tissue biopsies and can provide deeper insight into tumour heterogeneity. The robustness and reliability of LQB CNA analyses was evaluated. We performed retrospective CNA profiling using shallow whole-genome sequencing (sWGS) on paired plasma circulating cell-free DNA (cfDNA) and tissue DNA samples from routinely collected samples from paediatric patients (n = 128) representing different tumour entities, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, Wilms tumour, brain tumours and neuroblastoma. Overall, we observed a good concordance between CNAs in tissue DNA and cfDNA. The main cause of CNA discordance was found to be low cfDNA sample quality (i.e. the ratio of cfDNA (<700 bp) and high molecular weight DNA (>700 bp)). Furthermore, CNAs were observed that were present in cfDNA and not in tissue DNA, or vice-versa. In neuroblastoma samples, no false-positives or false-negatives were identified for the detection of the prognostic marker MYCN amplification. In future prospective studies, CNA analysis on LQBs that are of sufficient quality can serve as a complementary assay for CNA analysis on tissue biopsies, as either cfDNA or tissue DNA can contain CNAs that cannot be identified in the other biomaterial.
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BACKGROUND Significant heterogeneity of pediatric brain tumors poses major challenge on diagnostics. Therefore, we aimed to evaluate feasibility of methylation array in the diagnostic process. METHODS Methylation array (Infinium... more
BACKGROUND Significant heterogeneity of pediatric brain tumors poses major challenge on diagnostics. Therefore, we aimed to evaluate feasibility of methylation array in the diagnostic process. METHODS Methylation array (Infinium MethylationEPIC, Illumina) was performed on DNA extracted from fresh frozen tissue from prospective newly diagnosed and selected retrospective patients. Results from Heidelberg classifier (www.molecularneuropathology.org) were compared to the histological diagnosis and further genetic testing was performed to establish integrated morphological/molecular diagnosis. RESULTS Within years 2018–2019, we performed methylation array profiling of 102 samples consisting mainly of ependymoma, medulloblastoma high-grade and low-grade glioma. High calibrated score (>0.9) was achieved in 62 patients (61%). In 46 cases (74%) with score >0.9, the histological diagnosis matched the methylation class (MC). In the remaining cases (16) that were classified by histopathol...
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BACKGROUND Heterogeneous pathology in hemispheric low-grade gliomas (hemLGG) stress the importance of molecular testing in terms of prognosis prediction and targeted therapy options. METHODS Demographic data was collected and targeted... more
BACKGROUND Heterogeneous pathology in hemispheric low-grade gliomas (hemLGG) stress the importance of molecular testing in terms of prognosis prediction and targeted therapy options. METHODS Demographic data was collected and targeted genomic approach was employed in the single institutional study. RT-PCR was used to screen for KIAA1549-BRAF fusion and FGFR1 tyrosine-kinase domain duplication (FGFR1-ITD). Direct sequencing evaluated point mutations (BRAF ex15 and ex11, FGFR1 ex12 and ex14). Samples with no detected alteration were subjected to panel RNA-sequencing (FusionPlex Archer Diagnostics). RESULTS Within 2000–2019 were diagnosed 76 patients with hemLGG (median age 11.1y, range 0.0y–18.5y) comprising predominantly of ganglioglioma, dysembryoplastic neuroepithelial tumors, and diffuse astrocytoma. 40 % of hemLGG were characterized by BRAF alterations with over 2/3 of those cases harboring BRAF point mutations (two BRAFex11, 12 BRAFV600E). Notably, BRAF fusions were uncommon and...
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In the clinical management of pediatric solid tumors, histological examination of tumor tissue obtained by a biopsy remains the gold standard to establish a conclusive pathological diagnosis. The DNA methylation pattern of a tumor is... more
In the clinical management of pediatric solid tumors, histological examination of tumor tissue obtained by a biopsy remains the gold standard to establish a conclusive pathological diagnosis. The DNA methylation pattern of a tumor is known to correlate with the histopathological diagnosis across cancer types and is showing promise in the diagnostic workup of tumor samples. This methylation pattern can be detected in the cell-free DNA. Here, we provide proof-of-concept of histopathologic classification of pediatric tumors using cell-free reduced representation bisulfite sequencing (cf-RRBS) from retrospectively collected plasma and cerebrospinal fluid samples. We determined the correct tumor type in 49 out of 60 (81.6%) samples starting from minute amounts (less than 10 ng) of cell-free DNA. We demonstrate that the majority of misclassifications were associated with sample quality and not with the extent of disease. Our approach has the potential to help tackle some of the remaining ...
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Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in... more
Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.
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Research Interests: Medicine and Spinal Cord
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To investigate the difference between human umbilical vein endothelial cells (HUVEC) and human ocular microvascular endothelial cell (MVEC) gene expression, and to determine if these differences could improve the understanding of ocular... more
To investigate the difference between human umbilical vein endothelial cells (HUVEC) and human ocular microvascular endothelial cell (MVEC) gene expression, and to determine if these differences could improve the understanding of ocular angiogenic diseases.
Research Interests: British, Biology, Medicine, Cell Division, Humans, and 12 moreCapillaries, Endothelial Cells, Clinical Sciences, Optometry and Ophthalmology, Public health systems and services research, Iris, Gene expression profiling, Umbilical Vein PH, Choroid, real time polymerase chain reaction, Human Umbilical Vein Endothelial Cells, and Retinal vessels
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Research Interests: Genetics, Biology, Adolescent, Medicine, Cytogenetics, and 12 moreHumans, Female, Male, Pheochromocytoma, Children and Adolescents, Molecular Marker, Comparative Genomic Hybridization, Array Comparative Genomic Hybridization, Paraganglioma, Pathology and Oncology, Von Hippel Lindau disease, and Chromosome aberrations
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Research Interests: Dentistry, Biology, Immunohistochemistry, Cancer Genetics, Case Report, and 15 moreHumans, Child, Female, Male, Karyotyping, Bone marrow, Clinical Sciences, Adult, Bone Marrow Cells, Chromosome Banding, Combined Modality Therapy, liver metastases, Disease Free Survival, Liver neoplasms, and Fatal outcome
Warburg's metabolic hypothesis is based on the assumption that a cancer cell's respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not apply to all cancers, there is... more
Warburg's metabolic hypothesis is based on the assumption that a cancer cell's respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not apply to all cancers, there is some evidence proving that primarily abnormally functioning mitochondrial complexes are indeed related to cancer development. Thus, mutations in complex II (succinate dehydrogenase (SDH)) lead to the formation of pheochromocytoma (PHEO)/paraganglioma (PGL). Mutations in one of theSDHgenes (SDHxmutations) lead to succinate accumulation associated with very low fumarate levels, increased glutaminolysis, the generation of reactive oxygen species, and pseudohypoxia. This results in significant changes in signaling pathways (many of them dependent on the stabilization of hypoxia-inducible factor), including oxidative phosphorylation, glycolysis, specific expression profiles, as well as genomic instability and increased mutability resulting in tumor devel...
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10550Background: So far, and apart from minor adaptations, high-risk neuroblastoma patients have been treated uniformly by not taking biological features of the tumor into consideration. To mend th...