scholarly journals Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial ependymoma

2021 ◽  
Author(s):  
Philipp Sievers ◽  
Sophie C. Henneken ◽  
Christina Blume ◽  
Martin Sill ◽  
Daniel Schrimpf ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Distinct Group ◽  
Survival Times ◽  
Time To Progression ◽  
Molecular Alterations ◽  
Distinct Subset ◽  
Genome Wide ◽  
Cns Neoplasms ◽  
Tumor Types ◽  
Supratentorial Ependymoma

AbstractEpendymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of largely ependymoma-like tumors. Immunohistochemically, tumors were GFAP-positive and OLIG2- and SOX10-negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. Consistent with other fusion-positive ependymal groups, all tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Analysis of time to progression or recurrence revealed survival times comparable to those of patients with ZFTA:RELA-fused ependymoma. In summary, our findings suggest the existence of a novel group of supratentorial ependymomas that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

scholarly journals Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors

2021 ◽  
Author(s):  
Philipp Sievers ◽  
Sophie C. Henneken ◽  
Christina Blume ◽  
Martin Sill ◽  
Daniel Schrimpf ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Distinct Group ◽  
Progression Free Survival ◽  
Free Survival ◽  
Neuroepithelial Tumors ◽  
Molecular Alterations ◽  
Distinct Subset ◽  
Genome Wide ◽  
Cns Neoplasms ◽  
Tumor Types

AbstractEpendymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

Adaptive Convergence of Methylomes Reveals Epigenetic Drivers and Boosters of Repeated Relapses in Patient-matched Childhood Ependymomas and Identifies Targets for Anti-Recurrence Therapies

2021 ◽  
Author(s):  
Sibo Zhao ◽  
Jia Li ◽  
Huiyuan Zhang ◽  
Lin Qi ◽  
Yuchen Du ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pediatric Patients ◽  
Molecular Subtypes ◽  
Combined Treatment ◽  
Integrated Analysis ◽  
Driver Gene ◽  
Survival Times ◽  
Primary Tumors ◽  
Genome Wide ◽  
Dna Methylation Analysis

Abstract Ependymoma (EPN) is the third most common brain tumor in children and frequently recurs. Here, we report an integrated longitudinal analysis of epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses obtained from 10 pediatric patients to understand the mechanism of recurrences. Genome-wide DNA methylation analysis revealed stable molecular subtypes and convergent epigenetic reprogramming during serial relapses of the 5 RELA and 5 PFA EPNs that paralleled with elevated patient-derived orthotopic xenograft (PDOX) (13/27) formation in the late relapses. Differentially methylated CpGs (DMCs) preexisted in the primary tumors and persisted in the relapses (driver DMCs) were detected, ranging from 51 hypo-methylated in RELA to 148 hyper-methylated DMCs in PFA tumors; while newly acquired DMCs sustained in all the relapses but was absent in the primary tumors (booster DMCs) ranged from 38- 323 hyper-methylated DMCs in RELA and PFA EPNs, respectively. Integrated analysis of these DMC associated DNA methylation regions (DMRs) and RNAseq in both patient and PDOX tumors identified a small fraction of the differentially expressed genes (4.6±4.4% in RELA and 4.5±1.1% in PFA) as regulated by driver DMRs (e.g., up-regulated CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and booster DMRs (including the sole upregulated PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). Most these genes were novel to EPN relapses. Seven DMCs in RELA and 22 in PFA tumors were also identified as potential relapse predictors. Finally, integrating DNA methylation with histone modification identified LSD1 as a relapse driver gene. Combined treatment of a novel inhibitor SYC-836 with radiation significantly prolonged survival times in two PDOX models of recurrent PFA. This high-resolution epigenetic and genetic roadmap of EPN relapse and our 13 new PDOX models should significantly facilitate biological and preclinical studies of pediatric EPN recurrences.

scholarly journals Genome‐wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients

2019 ◽  
Vol 67 (2) ◽  
Author(s):  
Matthias Bleeke ◽  
Pascal Johann ◽  
Susanne Gröbner ◽  
Julia Alten ◽  
Gunnar Cario ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Pediatric Patients ◽  
Histiocytic Sarcoma ◽  
Genome Wide Analysis ◽  
Genome Wide

scholarly journals Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322983
Author(s):  
Benjamin Goeppert ◽  
Damian Stichel ◽  
Reka Toth ◽  
Sarah Fritzsche ◽  
Moritz Anton Loeffler ◽  
...  
Keyword(s):  
Treatment Options ◽  
Genetic Alterations ◽  
Integrative Analysis ◽  
Intermediate Form ◽  
Precursor Lesions ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Cells Of Origin ◽  
Sample Set ◽  
Methylation Profiling

ObjectiveA detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options.DesignWe analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling.ResultsPatients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but ROBO2 mutations occurred exclusively in invasive CCA and CTNNB1 mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin.ConclusionIntegrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.

scholarly journals Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2076-2086 ◽  
Author(s):  
Britta Will ◽  
Li Zhou ◽  
Thomas O. Vogler ◽  
Susanna Ben-Neriah ◽  
Carolina Schinke ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Genetic Alterations ◽  
Fish Analysis ◽  
Exact Nature ◽  
Clinical Relapse ◽  
Hematopoietic Stem ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Stem And Progenitor Cells ◽  
Specific Expansion

Abstract Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage−/CD34+/CD38−/CD90+) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% ± 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations.

scholarly journals NUTM1-Rearranged Neoplasms: A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations: An Updated Review

2021 ◽  
Vol 28 (6) ◽  
pp. 4485-4503
Author(s):  
Wenyi Luo ◽  
Todd M. Stevens ◽  
Phillip Stafford ◽  
Markku Miettinen ◽  
Zoran Gatalica ◽  
...  
Keyword(s):  
Hematologic Malignancies ◽  
Protein Product ◽  
Clinical Aspects ◽  
Chromosome 15 ◽  
Altered Expression ◽  
Molecular Alterations ◽  
Genome Wide ◽  
Bromodomain Proteins ◽  
Oncogenic Driver ◽  
Adnexal Tumors

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

scholarly journals Genome-wide sequence-based genotyping supports a nonhybrid origin of Castanea alabamensis

2019 ◽  
Author(s):  
M. Taylor Perkins ◽  
Tetyana Zhebentyayeva ◽  
Paul H. Sisco ◽  
J. Hill Craddock
Keyword(s):  
North American ◽  
Distinct Group ◽  
Morphological Diversity ◽  
Hybrid Origin ◽  
Putative Hybrid ◽  
Eastern United States ◽  
The North ◽  
Snp Data ◽  
Genome Wide ◽  
Conservation Concern

AbstractThe genus Castanea in North America contains multiple tree and shrub taxa of conservation concern. The two species within the group, American chestnut (Castanea dentata) and chinquapin (C. pumila sensu lato), display remarkable morphological diversity across their distributions in the eastern United States and southern Ontario. Previous investigators have hypothesized that hybridization between C. dentata and C. pumila has played an important role in generating morphological variation in wild populations. A putative hybrid taxon, Castanea alabamensis, was identified in northern Alabama in the early 20th century; however, the question of its hybridity has been unresolved. We tested the hypothesized hybrid origin of C. alabamensis using genome-wide sequence-based genotyping of C. alabamensis, all currently recognized North American Castanea taxa, and two Asian Castanea species at >100,000 single-nucleotide polymorphism (SNP) loci. With these data, we generated a high-resolution phylogeny, tested for admixture among taxa, and analyzed population genetic structure of the study taxa. Bayesian clustering and principal components analysis provided no evidence of admixture between C. dentata and C. pumila in C. alabamensis genomes. Phylogenetic analysis of genome-wide SNP data indicated that C. alabamensis forms a distinct group within C. pumila sensu lato. Our results are consistent with the model of a nonhybrid origin for C. alabamensis. Our finding of C. alabamensis as a genetically and morphologically distinct group within the North American chinquapin complex provides further impetus for the study and conservation of the North American Castanea species.

scholarly journals An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer

2020 ◽  
Author(s):  
Athea Vichas ◽  
Naomi T. Nkinsi ◽  
Amanda Riley ◽  
Phoebe C.R. Parrish ◽  
Fujiko Duke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Hippo Pathway ◽  
Spindle Assembly ◽  
Human Lung Cancer ◽  
Precision Oncology ◽  
Cancer Driver ◽  
Molecular Alterations ◽  
Pathway Gene ◽  
Genome Wide

ABSTRACTAdvances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor’s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred by lung cancer driver variants of KRAS, EGFR, and RIT1. Integrative analysis of genome-wide CRISPR screens in isogenic cell lines identified shared and unique vulnerabilities of each oncogene. The non-identical landscape of dependencies underscores the importance of genotype-guided therapies to maximize tumor responses. Combining genetic screening data with small molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. This sensitivity may be related to a novel role of RIT1 in mitosis; we find that oncogenic RIT1M90I alters mitotic timing via weakening of the spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutant RIT1 with loss of Hippo pathway genes. In human lung cancer, RIT1 mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenic RIT1-cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

169 The influence of histology on time to progression after irradiation for localized ependymoma in pediatric patients

1999 ◽  
Vol 45 (3) ◽  
pp. 235 ◽  
Author(s):  
T.E. Merchant ◽  
R.A. Sanford ◽  
J.M. Boyett ◽  
W. Wang ◽  
R.L. Heideman ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Time To Progression

scholarly journals Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study

2018 ◽  
Vol 36 (6) ◽  
pp. 536-542 ◽  
Author(s):  
John D. Hainsworth ◽  
Funda Meric-Bernstam ◽  
Charles Swanton ◽  
Herbert Hurwitz ◽  
David R. Spigel ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Targeted Therapy ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Molecular Alterations ◽  
Epidermal Growth ◽  
Tumor Types ◽  
Murine Sarcoma

Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2–amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non–small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.

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