42 results on '"Brozou T"'
Search Results
2. P312: EMPLOYING WHOLE GENOME OPTICAL MAPPING TO CHARACTERIZE THE LANDSCAPE OF STRUCTURAL VARIANTS IN B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA
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Brandes, D., primary, Brozou, T., additional, Soura, S., additional, Bergmann, A., additional, Fischer, U., additional, Borkhardt, A., additional, and Wagener, R., additional
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- 2022
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3. P313: RECURRENT PATHOGENIC GERMLINE CHEK2 VARIANTS IN PEDIATRIC PATIENTS WITH HEMATOLOGICAL MALIGNANCIES
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Brozou, T., primary, Wagener, R., additional, Fischer, U., additional, and Borkhardt, A., additional
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- 2022
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4. Patterns and temporal trends in the incidence of childhood and adolescence cancer in Cyprus 1998-2017: a population-based study from the Cyprus Pediatric Oncology Registry
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Loizou L, Demetriou A, Erdmann F, Borkhardt A, Brozou T, Sharp L, McNally R
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- 2022
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5. Bauchumfangsvermehrung und Hemihypertrophie
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Escherich, C., primary, Schaper, J., additional, Beygo, J., additional, Borkhardt, A., additional, and Brozou, T., additional
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- 2020
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6. Acalculous cholecystitis or biliary dyskinesia for Epstein-Barr virus gallbladder involvement?
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Fretzayas, A. Moustaki, M. Attilakos, A. Brozou, T. Nicolaidou, P.
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hemic and lymphatic diseases - Abstract
We present two patients with Epstein-Barr virus (EBV) infection related to gallbladder involvement. Such an association is already known as EBV induced acalculous cholecystitis, diagnosed on the basis of ultrasonographic findings. In our patients, radioisotopic cholescintigraphy was also performed and it showed that gallbladder was visualized in both patients in contrast to that what can be observed in cases of cholecystitis. However, the value of ejection fraction was compatible with biliary dyskinesia. We, therefore, consider that impaired gallbladder contractility in EBV infection cases may actually represent biliary dyskinesia and not acalculous cholecystitis taking into account the radioisotopic findings and the self limited course of the disorder.
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- 2014
7. Postoperative spinal infection mimicking systemic vasculitis with titanium-spinal implants
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Sakellariou, V.I. Atsali, E. Starantzis, K. Batistaki, C. Brozou, T. Pantos, P. Stathopoulos, K. Soultanis, K.
- Abstract
Background: Secondary systemic vasculitis after posterior spinal fusion surgery is rare. It is usually related to over-reaction of immune-system, to genetic factors, toxicity, infection or metal allergies.Case Description: A 14 year-old girl with a history of extended posterior spinal fusion due to idiopathic scoliosis presented to our department with diffuse erythema and nephritis (macroscopic hemuresis and proteinuria) 5 months post surgery. The surgical trauma had no signs of inflammation or infection. The blood markers ESR and CRP were increased. Skin tests were positive for nickel allergy, which is a content of titanium alloy. The patient received corticosteroids systematically (hydrocortisone 10 mg) for 6 months, leading to total recess of skin and systemic reaction. However, a palpable mass close to the surgical wound raised the suspicion of a late infection. The patient had a second surgery consisting of surgical debridement and one stage revision of posterior spinal instrumentation. Intraoperative cultures were positive to Staphylococcus aureus. Intravenous antibiotics were administered. The patient is now free of symptoms 24 months post revision surgery without any signs of recurrence of either vasculitis or infection.Literature Review: Systemic vasculitis after spinal surgery is exceptionally rare. Causative factors are broad and sometimes controversial. In general, it is associated with allergy to metal ions. This is usually addressed with metal on metal total hip bearings. In spinal surgery, titanium implants are considered to be inert and only few reports have presented cases with systemic vasculitides. Therefore, other etiologies of immune over-reaction should always be considered, such as drug toxicity, infection, or genetic predisposition.Purposes and Clinical Relevance: Our purpose was to highlight the difficulties during the diagnostic work-up for systemic vasculitis and management in cases of posterior spinal surgery. © 2011 Sakellariou et al; licensee BioMed Central Ltd.
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- 2011
8. MRSA blistering distal dactylitis and review of reported cases
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Fretzayas, A. Moustaki, M. Tsagris, V. Brozou, T. Nicolaidou, P.
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integumentary system - Abstract
We describe a 6-month-old infant with blistering distal dactylitis. Bacterial culture from the skin lesion grew methicillin resistant Staphylococcus aureus. No carriage of this bacterial agent was identified in her family. She responded to vancomycin administration and incision and drainage of the lesion. This is the first reported case of methicillin resistant Staphylococcus aureus-associated blistering distal dactylitis in an infant. © 2011 Wiley Periodicals, Inc.
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- 2011
9. Postoperative spinal infection mimicking systemic vasculitis with titanium-spinal implants.
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Sakellariou VI, Atsali E, Starantzis K, Batistaki C, Brozou T, Pantos P, Stathopoulos K, and Soultanis K
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- 2011
10. Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma
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Anne Schedel, Ulrike Anne Friedrich, Mina N. F. Morcos, Rabea Wagener, Juha Mehtonen, Titus Watrin, Claudia Saitta, Triantafyllia Brozou, Pia Michler, Carolin Walter, Asta Försti, Arka Baksi, Maria Menzel, Peter Horak, Nagarajan Paramasivam, Grazia Fazio, Robert J Autry, Stefan Fröhling, Meinolf Suttorp, Christoph Gertzen, Holger Gohlke, Sanil Bhatia, Karin Wadt, Kjeld Schmiegelow, Martin Dugas, Daniela Richter, Hanno Glimm, Merja Heinäniemi, Rolf Jessberger, Gianni Cazzaniga, Arndt Borkhardt, Julia Hauer, Franziska Auer, Schedel, A, Friedrich, U, Morcos, M, Wagener, R, Mehtonen, J, Watrin, T, Saitta, C, Brozou, T, Michler, P, Walter, C, Forsti, A, Baksi, A, Menzel, M, Horak, P, Paramasivam, N, Fazio, G, Autry, R, Frohling, S, Suttorp, M, Gertzen, C, Gohlke, H, Bhatia, S, Wadt, K, Schmiegelow, K, Dugas, M, Richter, D, Glimm, H, Heinaniemi, M, Jessberger, R, Cazzaniga, G, Borkhardt, A, Hauer, J, and Auer, F
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germline cancer predisposition ,cohesin complex ,Organic Chemistry ,acute lymphoblastic leukemia ,trio sequencing ,RAD21 ,General Medicine ,Catalysis ,ddc ,Computer Science Applications ,Inorganic Chemistry ,ddc:540 ,Article ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.
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- 2022
11. Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment
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Triantafyllia Brozou, Jelena Lazic, Gabor G. Kovacs, Maria E.V. Alonso, Chi Kong Li, Gábor Ottóffy, Ondrej Hrusak, Pernilla Grillner, Adriana Balduzzi, Tomas Kalina, Sarah Elitzur, Joshua Wolf, Massimo Provenzi, Hany Ariffin, Ajay Vora, Jan Stary, Barbara Buldini, Nerea Domínguez-Pinilla, Karin Mellgren, Allen Eng Juh Yeoh, Valentino Conter, Rob Pieters, Jutte van der Werff ten Bosch, Luciano Dalla-Pozza, Jean-Pierre Bourquin, Martin Schrappe, Martin Stanulla, Owen P. Smith, Kjeld Schmiegelow, Roula Farah, Susana Rives, Andishe Attarbaschi, Carmelo Rizzari, Maria S. Felice, Atsushi Manabe, Gabriele Escherich, A Kolenova, María del Pozo Carlavilla, Melchior Lauten, Jan Styczyński, Arndt Borkhardt, Clinical sciences, Growth and Development, Pediatrics, Hrusak, O, Kalina, T, Wolf, J, Balduzzi, A, Provenzi, M, Rizzari, C, Rives, S, del Pozo Carlavilla, M, Alonso, M, Dominguez-Pinilla, N, Bourquin, J, Schmiegelow, K, Attarbaschi, A, Grillner, P, Mellgren, K, van der Werff ten Bosch, J, Pieters, R, Brozou, T, Borkhardt, A, Escherich, G, Lauten, M, Stanulla, M, Smith, O, Yeoh, A, Elitzur, S, Vora, A, Li, C, Ariffin, H, Kolenova, A, Dallapozza, L, Farah, R, Lazic, J, Manabe, A, Styczynski, J, Kovacs, G, Ottoffy, G, Felice, M, Buldini, B, Conter, V, Stary, J, and Schrappe, M
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0301 basic medicine ,Male ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Pneumonia, Viral ,Anticancer chemotherapy ,Antineoplastic Agents ,Disease ,Asymptomatic ,03 medical and health sciences ,Betacoronavirus ,0302 clinical medicine ,Children ,Diabetes mellitus ,Neoplasms ,Surveys and Questionnaires ,medicine ,Humans ,Viral ,Pediatrics, Perinatology, and Child Health ,Young adult ,Child ,Pandemics ,immunosuppression ,SARS-CoV-2 ,business.industry ,Incidence (epidemiology) ,COVID-19 ,Pneumonia ,medicine.disease ,Obesity ,COVID-19 Drug Treatment ,030104 developmental biology ,Oncology ,El Niño ,030220 oncology & carcinogenesis ,Female ,Immunosuppression ,Coronavirus Infections ,medicine.symptom ,business - Abstract
INTRODUCTION: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia. AIM AND METHODS: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey. RESULTS: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19. CONCLUSION: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.
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- 2020
12. ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.
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Elitzur S, Shiloh R, Loeffen JLC, Pastorczak A, Takagi M, Bomken S, Baruchel A, Lehrnbecher T, Tasian SK, Abla O, Arad-Cohen N, Astigarraga I, Ben-Harosh M, Bodmer N, Brozou T, Ceppi F, Chugaeva L, Dalla Pozza L, Ducassou S, Escherich G, Farah R, Gibson A, Hasle H, Hoveyan J, Jacoby E, Jazbec J, Junk S, Kolenova A, Lazic J, Lo Nigro L, Mahlaoui N, Miller L, Papadakis V, Pecheux L, Pillon M, Sarouk I, Stary J, Stiakaki E, Strullu M, Tran TH, Ussowicz M, Verdu-Amoros J, Wakulinska A, Zawitkowska J, Stoppa-Lyonnet D, Taylor AM, Shiloh Y, Izraeli S, Minard-Colin V, Schmiegelow K, Nirel R, Attarbaschi A, and Borkhardt A
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- Humans, Child, Male, Female, Adolescent, Child, Preschool, Infant, Young Adult, Adult, Ataxia Telangiectasia Mutated Proteins genetics, Ataxia Telangiectasia genetics, Ataxia Telangiectasia complications, Ataxia Telangiectasia mortality, Hematologic Neoplasms genetics, Hematologic Neoplasms mortality, Germ-Line Mutation
- Abstract
Abstract: Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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13. Optical genome mapping identifies structural variants in potentially new cancer predisposition candidate genes in pediatric cancer patients.
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Wagener R, Brandes D, Jung M, Huetzen MA, Bergmann AK, Panier S, Picard D, Fischer U, Jachimowicz RD, Borkhardt A, and Brozou T
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- Child, Humans, Genetic Predisposition to Disease, Mutation, Chromosome Mapping, Germ-Line Mutation, Neoplasms genetics
- Abstract
Genetic predisposition is one of the major risk factors for pediatric cancer, with ~10% of children being carriers of a predisposing germline alteration. It is likely that this is the tip of the iceberg and many children are underdiagnosed, as most of the analysis focuses on single or short nucleotide variants, not considering the full spectrum of DNA alterations. Hence, we applied optical genome mapping (OGM) to our cohort of 34 pediatric cancer patients to perform an unbiased germline screening and analyze the frequency of structural variants (SVs) and their impact on cancer predisposition. All children were clinically highly suspicious for germline alterations (concomitant conditions or congenital anomalies, positive family cancer history, particular cancer type, synchronous or metachronous tumors), but whole exome sequencing (WES) had failed to detect pathogenic variants in cancer predisposing genes. OGM detected a median of 49 rare SVs (range 27-149) per patient. By analysis of 18 patient-parent trios, we identified three de novo SVs. Moreover, we discovered a likely pathogenic deletion of exon 3 in the known cancer predisposition gene BRCA2, and identified a duplication in RPA1, which might represent a new cancer predisposition gene. We conclude that optical genome mapping is a suitable tool for detecting potentially predisposing SVs in addition to WES in pediatric cancer patients., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
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- 2024
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14. Hyperdiploid acute lymphoblastic leukemia in children with LZTR1 germline variants.
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Zipper L, Wagener R, Fischer U, Hoffmann A, Yasin L, Brandes D, Soura S, Anwar A, Walter C, Varghese J, Hauer J, Auer F, Bhatia S, Dugas M, Junk SV, Stanulla M, Haas OA, Borkhardt A, Reiff T, and Brozou T
- Abstract
Competing Interests: The authors declare no conflict of interest.
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- 2024
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15. Integrative multi-omics reveals two biologically distinct groups of pilocytic astrocytoma.
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Picard D, Felsberg J, Langini M, Stachura P, Qin N, Macas J, Reiss Y, Bartl J, Selt F, Sigaud R, Meyer FD, Stefanski A, Stühler K, Roque L, Roque R, Pandyra AA, Brozou T, Knobbe-Thomsen C, Plate KH, Roesch A, Milde T, Reifenberger G, Leprivier G, Faria CC, and Remke M
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- Child, Humans, Multiomics, Proteomics, Action Potentials, Astrocytoma genetics, Brain Neoplasms genetics
- Abstract
Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene fusions or activating mutations. While 5-year overall survival rates exceed 95%, tumor recurrence or progression constitutes a major clinical challenge in incompletely resected tumors. Here, we used similarity network fusion (SNF) analysis in an integrative multi-omics approach employing RNA transcriptomic and mass spectrometry-based proteomic profiling to molecularly characterize PA tissue samples from 62 patients. Thereby, we uncovered that PAs segregated into two molecularly distinct groups, namely, Group 1 and Group 2, which were validated in three non-overlapping cohorts. Patients with Group 1 tumors were significantly younger and showed worse progression-free survival compared to patients with group 2 tumors. Ingenuity pathways analysis (IPA) and gene set enrichment analysis (GSEA) revealed that Group 1 tumors were enriched for immune response pathways, such as interferon signaling, while Group 2 tumors showed enrichment for action potential and neurotransmitter signaling pathways. Analysis of immune cell-related gene signatures showed an enrichment of infiltrating T Cells in Group 1 versus Group 2 tumors. Taken together, integrative multi-omics of PA identified biologically distinct and prognostically relevant tumor groups that may improve risk stratification of this single pathway driven tumor type., (© 2023. The Author(s).)
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- 2023
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16. A clinical screening tool to detect genetic cancer predisposition in pediatric oncology shows high sensitivity but can miss a substantial percentage of affected children.
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Friedrich UA, Bienias M, Zinke C, Prazenicova M, Lohse J, Jahn A, Menzel M, Langanke J, Walter C, Wagener R, Brozou T, Varghese J, Dugas M, Erlacher M, Schröck E, Suttorp M, Borkhardt A, Hauer J, and Auer F
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- Humans, Child, Genetic Predisposition to Disease, Early Detection of Cancer, Genetic Testing, Genotype, Germ-Line Mutation genetics, Neoplasms diagnosis, Neoplasms genetics, Neoplasms pathology, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics
- Abstract
Purpose: Clinical checklists are the standard of care to determine whether a child with cancer shows indications for genetic testing. Nevertheless, the efficacy of these tests to reliably detect genetic cancer predisposition in children with cancer is still insufficiently investigated., Methods: We assessed the validity of clinically recognizable signs to identify cancer predisposition by correlating a state-of-the-art clinical checklist to the corresponding exome sequencing analysis in an unselected single-center cohort of 139 child-parent data sets., Results: In total, one-third of patients had a clinical indication for genetic testing according to current recommendations, and 10.1% (14 of 139) of children harbored a cancer predisposition. Of these, 71.4% (10 of 14) were identified through the clinical checklist. In addition, >2 clinical findings in the checklist increased the likelihood to identifying genetic predisposition from 12.5% to 50%. Furthermore, our data revealed a high rate of genetic predisposition (40%, 4 of 10) in myelodysplastic syndrome cases, while no (likely) pathogenic variants were identified in the sarcoma and lymphoma group., Conclusion: In summary, our data show high checklist sensitivity, particularly in identifying childhood cancer predisposition syndromes. Nevertheless, the checklist used here also missed 29% of children with a cancer predisposition, highlighting the drawbacks of sole clinical evaluation and underlining the need for routine germline sequencing in pediatric oncology., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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17. Optical Genome Mapping Identifies Novel Recurrent Structural Alterations in Childhood ETV6::RUNX1+ and High Hyperdiploid Acute Lymphoblastic Leukemia.
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Brandes D, Yasin L, Nebral K, Ebler J, Schinnerl D, Picard D, Bergmann AK, Alam J, Köhrer S, Haas OA, Attarbaschi A, Marschall T, Stanulla M, Borkhardt A, Brozou T, Fischer U, and Wagener R
- Abstract
The mutational landscape of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common pediatric cancer, is not fully described partially because commonly applied short-read next generation sequencing has a limited ability to identify structural variations. By combining comprehensive analysis of structural variants (SVs), single-nucleotide variants (SNVs), and small insertions-deletions, new subtype-defining and therapeutic targets may be detected. We analyzed the landscape of somatic alterations in 60 pediatric patients diagnosed with the most common BCP-ALL subtypes, ETV6::RUNX1 + and classical hyperdiploid (HD), using conventional cytogenetics, single nucleotide polymorphism (SNP) array, whole exome sequencing (WES), and the novel optical genome mapping (OGM) technique. Ninety-five percent of SVs detected by cytogenetics and SNP-array were verified by OGM. OGM detected an additional 677 SVs not identified using the conventional methods, including (subclonal) IKZF1 deletions. Based on OGM, ETV6::RUNX1 + BCP-ALL harbored 2.7 times more SVs than HD BCP-ALL, mainly focal deletions. Besides SVs in known leukemia development genes ( ETV6 , PAX5 , BTG1, CDKN2A ), we identified 19 novel recurrently altered regions (in n ≥ 3) including 9p21.3 ( FOCAD/HACD4 ), 8p11.21 ( IKBKB ), 1p34.3 ( ZMYM1 ), 4q24 ( MANBA ), 8p23.1 ( MSRA ), and 10p14 ( SFMBT2 ), as well as ETV6::RUNX1+ subtype-specific SVs (12p13.1 ( GPRC5A ), 12q24.21 ( MED13L ), 18q11.2 ( MIB1 ), 20q11.22 ( NCOA6 )). We detected 3 novel fusion genes ( SFMBT2::DGKD, PDS5B::STAG2, and TDRD5::LPCAT2 ), for which the sequence and expression were validated by long-read and whole transcriptome sequencing, respectively. OGM and WES identified double hits of SVs and SNVs ( ETV6 , BTG1 , STAG2 , MANBA , TBL1XR1 , NSD2 ) in the same patient demonstrating the power of the combined approach to define the landscape of genomic alterations in BCP-ALL., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
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- 2023
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18. Reply to: Comments on "The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients".
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Borkhardt A, Wagener R, and Brozou T
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- Child, Humans, Germ Cells metabolism, Checkpoint Kinase 2 genetics, Ataxia Telangiectasia Mutated Proteins, Phosphorylation, DNA Damage, Cell Cycle Proteins metabolism, Protein Serine-Threonine Kinases genetics, Neoplasms genetics
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- 2023
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19. Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency.
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Gallon R, Phelps R, Hayes C, Brugieres L, Guerrini-Rousseau L, Colas C, Muleris M, Ryan NAJ, Evans DG, Grice H, Jessop E, Kunzemann-Martinez A, Marshall L, Schamschula E, Oberhuber K, Azizi AA, Baris Feldman H, Beilken A, Brauer N, Brozou T, Dahan K, Demirsoy U, Florkin B, Foulkes W, Januszkiewicz-Lewandowska D, Jones KJ, Kratz CP, Lobitz S, Meade J, Nathrath M, Pander HJ, Perne C, Ragab I, Ripperger T, Rosenbaum T, Rueda D, Sarosiek T, Sehested A, Spier I, Suerink M, Zimmermann SY, Zschocke J, Borthwick GM, Wimmer K, Burn J, Jackson MS, and Santibanez-Koref M
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- Humans, Microsatellite Instability, Genotype, DNA Mismatch Repair genetics, Mismatch Repair Endonuclease PMS2 genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms diagnosis, Brain Neoplasms diagnosis
- Abstract
Background & Aims: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood., Methods: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls., Results: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor., Conclusions: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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20. Functional damaging germline variants in ETV6, IKZF1, PAX5 and RUNX1 predisposing to B-cell precursor acute lymphoblastic leukemia.
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Wagener R, Elitzur S, Brozou T, and Borkhardt A
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- Child, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Polymorphism, Genetic, ETS Translocation Variant 6 Protein, Core Binding Factor Alpha 2 Subunit genetics, Ikaros Transcription Factor genetics, PAX5 Transcription Factor genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Proteins c-ets genetics
- Abstract
Recent genome-wide studies have demonstrated that a significant proportion of children with cancer carry predisposing germline variants, with varying incidence according to cancer type. In general, there is a lower incidence of underlying germline predisposing variants among patients with B-cell acute lymphoblastic leukemia (B-ALL) compared to other types of cancer, but higher rates may be found in patients with specific leukemia subtypes. Two categories of ALL-predisposing variants have been described: common polymorphisms, conferring low-penetrance ALL susceptibility, and rare variants, conferring high-penetrance ALL susceptibility. Variants in genes encoding hematopoietic transcription factors are an example of the latter, and include ETV6, IKZF1, PAX5 and RUNX1. Here, we present an overview of the germline variants detected in patients with B-ALL in these four genes and a summary of functional studies analyzing the impacts of these variants upon protein function, and hence their effects with regard to leukemia predisposition. Furthermore, we review specific clinical characteristics of patients with B-ALL, including specific features of the patient or family history and associated somatic genetic characteristics, which are suggestive of underlying germline alterations in one of these genes. This review may be of assistance in the interpretation of patient genetic germline findings, made even more challenging by the absence of a suggestive family history or by an unknown familial cancer history. Despite a low incidence of underlying germline alterations in ETV6, IKZF1, PAX5 and RUNX1 in patients with B-ALL, identification of an underlying ALL predisposition syndrome is relevant to the clinical management of patients and their relatives, as the latter are also at risk of developing cancer., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
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- 2023
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21. The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients.
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Wagener R, Walter C, Auer F, Alzoubi D, Hauer J, Fischer U, Varghese J, Dugas M, Borkhardt A, and Brozou T
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- Adult, Child, Female, Humans, Checkpoint Kinase 2 genetics, DNA Damage genetics, Genetic Predisposition to Disease, Germ Cells, Germ-Line Mutation, Breast Neoplasms, Neoplasms genetics
- Abstract
Predisposing CHEK2 germline variants are associated with various adult-type malignancies, whereas their impact on cancer susceptibility in childhood cancer is unclear. To understand the frequency of germline variants in the CHEK2 gene and their impact on pediatric malignancies, we used whole-exome sequencing to search for CHEK2 variants in the germlines of 418 children diagnosed with cancer in our clinics. Moreover, we performed functional analysis of the pathogenic CHEK2 variants to analyze the effect of the alterations on CHK2 protein function. We detected a CHEK2 germline variant in 32/418 (7.7%) pediatric cancer patients and 46.8% of them had leukemia. Functional analysis of the pathogenic variants revealed that 5 pathogenic variants impaired CHK2 protein function. 6/32 patients carried one of these clearly damaging CHEK2 variants and two of them harbored a matching family history of cancer. In conclusion, we detected germline CHEK2 variants in 7.7% of all pediatric cancer patients, of which a minority but still relevant fraction of approximately 20% had a profound impact on protein expression or its phosphorylation after irradiation-induced DNA damage. Accordingly, we conclude that CHEK2 variants increase the risk for not only adult-onset but also pediatric cancer., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
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- 2023
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22. Noncancer-related Secondary Findings in a Cohort of 231 Children With Cancer and Their Parents.
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Wagener R, Walter C, Surowy HM, Brandes D, Soura S, Alzoubi D, Yasin L, Fischer U, Dugas M, Borkhardt A, and Brozou T
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- Humans, Child, United States, KCNQ1 Potassium Channel genetics, Exome Sequencing, Parents, Genetic Testing, Neoplasms genetics, Cardiovascular Diseases
- Abstract
Application of next-generation sequencing may lead to the detection of secondary findings (SF) not related to the initially analyzed disease but to other severe medically actionable diseases. However, the analysis of SFs is not yet routinely performed. We mined whole-exome sequencing data of 231 pediatric cancer patients and their parents who had been treated in our center for the presence of SFs. By this approach, we identified in 6 children (2.6%) pathogenic germline variants in 5 of the noncancer-related genes on the American College of Medical Genetics and Genomics (ACMG) SF v3.0 list, of which the majority were related to cardiovascular diseases ( RYR2 , MYBPC3 , KCNQ1 ). Interestingly, only the patient harboring the KCNQ1 variant showed at the time point of the analysis signs of the related Long QT syndrome. Moreover, we report 3 variants of unknown significance which, although not classified as pathogenic, have been reported in the literature to occur in individuals with the respective disease. While the frequency of patients with SFs is low, the impact of such findings on the patients' life is enormous, with regard to the potential prevention of life-threatening diseases. Hence, we are convinced that such actionable SF should be routinely analyzed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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23. Resolving inherited and de novo germline predisposing sequence variants by means of whole exome trio analyses in childhood hematological malignancies.
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Brozou T, Yasin L, Brandes D, Picard D, Walter C, Varghese J, Dugas M, Fischer U, Borkhardt A, and Haas OA
- Abstract
Molecular screening tools have significantly eased the assessment of potential germline susceptibility factors that may underlie the development of pediatric malignancies. Most of the hitherto published studies utilize the comparative analyses of the respective patients' germline and tumor tissues for this purpose. Since this approach is not able to discriminate between de novo and inherited sequence variants, we performed whole exome trio analyses in a consecutive series of 131 children with various forms of hematologic malignancies and their parents. In total, we identified 458 de novo variants with a range from zero to 28 (median value = 3) per patient, although most of them (58%) had only up to three per exome. Overall, we identified bona fide cancer predisposing alterations in five of the investigated 131 (3.8%) patients. Three of them had de novo pathogenic lesions in the SOS1 , PTPN11 and TP53 genes and two of them parentally inherited ones in the STK11 and PMS2 genes that are specific for a Peutz-Jeghers and a constitutional mismatch repair deficiency (CMMRD) syndrome, respectively. Notwithstanding that we did not identify a disease-specific alteration in the two cases with the highest number of de novo variants, one of them developed two almost synchronous malignancies: a myelodysplastic syndrome and successively within two months a cerebral astrocytoma. Moreover, we also found that the rate of de novo sequence variants in the offspring increased especially with the age of the father, but less so with that of the mother. We therefore conclude that trio analyses deliver an immediate overview about the inheritance pattern of the entire spectrum of sequence variants, which not only helps to securely identify the de novo or inherited nature of genuinely disease-related lesions, but also of all other less obvious variants that in one or the other way may eventually advance our understanding of the disease process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Brozou, Yasin, Brandes, Picard, Walter, Varghese, Dugas, Fischer, Borkhardt and Haas.)
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- 2023
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24. Patterns and temporal trends in the incidence of childhood and adolescence cancer in Cyprus 1998-2017: A population-based study from the Cyprus Paediatric Oncology Registry.
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Loizou L, Demetriou A, Erdmann F, Borkhardt A, Brozou T, Sharp L, and McNally R
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- Adolescent, Adult, Child, Child, Preschool, Cyprus epidemiology, Humans, Incidence, Infant, Infant, Newborn, Registries, Young Adult, Central Nervous System Neoplasms, Lymphoma, Neoplasms etiology
- Abstract
Background: Despite its rarity, cancer in children and adolescents (CAC) is a major health issue worldwide. The lack of appropriate cancer registries is an obstacle for defining its incidence and survival, and informing cancer control. As in Cyprus, CAC epidemiology has not previously been comprehensively examined, we determined incidence rates and temporal trends of cancer in the 0-19 age group during 1998-2017., Methods: We established the population based Paediatric Oncology Registry of Cyprus (PORCY) for the period 1998-2017. World age standardised incidence rate per million children and adolescents per year (ASRW) were calculated and time trends were assessed using Joinpoint regression analysis. Comparisons were made with other countries using the International Incidence of Childhood Cancer, third volume., Results: For all cancers combined, for ages 0-19-years, ASRW was 203.54 (95% CI 189.49, 217.59) one of the highest rates globally. The most frequent CAC were leukaemias followed by lymphomas, specified epithelial neoplasms and central nervous system tumours, differing to what is described in most other countries. For all cancers, both combined and individual types, except thyroid carcinoma (where incidence was rising), no significant temporal variation was found., Conclusions: To inform cancer control activities, we conducted the first ever population-based epidemiological study of childhood and adolescent cancer (0-19 years) in Cyprus. The striking findings indicate high overall incidence rates that are among the world's highest, a higher frequency of lymphomas and thyroid cancer than brain tumours, and rising incidence for thyroid, but not for other, cancers. These novel findings, will help the formulation of hypotheses to provide explanation for the high rates for all CAC in Cyprus and may contribute to the global efforts for improving prevention of cancer in this age group., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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25. Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.
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Schedel A, Friedrich UA, Morcos MNF, Wagener R, Mehtonen J, Watrin T, Saitta C, Brozou T, Michler P, Walter C, Försti A, Baksi A, Menzel M, Horak P, Paramasivam N, Fazio G, Autry RJ, Fröhling S, Suttorp M, Gertzen C, Gohlke H, Bhatia S, Wadt K, Schmiegelow K, Dugas M, Richter D, Glimm H, Heinäniemi M, Jessberger R, Cazzaniga G, Borkhardt A, Hauer J, and Auer F
- Subjects
- Apoptosis, Cell Line, Tumor, Child, De Lange Syndrome genetics, G2 Phase Cell Cycle Checkpoints, Germ Cells metabolism, Humans, Mutation, Phenotype, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, DNA-Binding Proteins genetics, Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.
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- 2022
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26. Multimodal Treatment of Nasopharyngeal Carcinoma in Children, Adolescents and Young Adults-Extended Follow-Up of the NPC-2003-GPOH Study Cohort and Patients of the Interim Cohort.
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Römer T, Franzen S, Kravets H, Farrag A, Makowska A, Christiansen H, Eble MJ, Timmermann B, Staatz G, Mottaghy FM, Bührlen M, Hagenah U, Puzik A, Driever PH, Greiner J, Jorch N, Tippelt S, Schneider DT, Kropshofer G, Overbeck TR, Christiansen H, Brozou T, Escherich G, Becker M, Friesenbichler W, Feuchtinger T, Puppe W, Heussen N, Hilgers RD, and Kontny U
- Abstract
Nasopharyngeal carcinoma (NPC) in children and young adults has been treated within two consecutive prospective trials in Germany, the NPC-91 and the NPC-2003 study of the German Society of Pediatric Oncology and Hematology (GPOH). In these studies, multimodal treatment with induction chemotherapy, followed by radio (chemo)therapy and interferon-beta maintenance, yielded promising survival rates even after adapting total radiation doses to tumor response. The outcome of 45 patients in the NPC-2003 study was reassessed after a median follow-up of 85 months. In addition, we analyzed 21 further patients after closure of the NPC-2003 study, recruited between 2011 and 2017, and treated as per the NPC-2003 study protocol. The EFS and OS of 66 patients with locoregionally advanced NPC were 93.6% and 96.7%, respectively, after a median follow-up of 73 months. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy; none relapsed. In young patients with advanced locoregional NPC, excellent long-term survival rates can be achieved by multimodal treatment, including interferon-beta. Radiation doses may be reduced in patients with complete remission after induction chemotherapy and may limit radiogenic late effects.
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- 2022
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27. Second-look surgery after pediatric brain tumor resection - Single center analysis of morbidity and volumetric efficacy.
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Schmitz AK, Munoz-Bendix C, Remke M, Brozou T, Borkhardt A, Hänggi D, and Beez T
- Abstract
Introduction: Postoperative residual tumor can occur for intentional or unintentional reasons. Decision-making regarding second-look surgery has to weigh molecular biology, probability of total resection and prognostic relevance against potential additional morbidity. In interdisciplinary tumor boards the neurosurgeon has to estimate risk and efficacy of second-look surgery in individual cases, based on precise data., Research Question: Aim of this study was to provide such data by analyzing morbidity and volumetric efficacy of second-look surgery at a designated pediatric neuro-oncology unit., Material and Methods: Children who received second-look surgery in 2007-2018 after incomplete resections were analyzed retrospectively. Measurements were performed on early postoperative magnetic resonance imaging, comparing axial diameter-based measurement as well as computer-assisted volumetric analysis., Results: 59 patients (37% of the overall cohort; 21 female; mean age: 8 ± 5 years) received a subtotal (n = 35) or near total (n = 24) resection. After interdisciplinary case review, 12 of these patients received second-look surgery mainly for residual ependymoma. This led to further tumor volume reduction in all cases (new degrees of resection: subtotal = 2, near total = 6, gross total = 4). No new permanent morbidity or perioperative mortality was observed., Discussion and Conclusion: Second-look surgery did not increase mortality and permanent morbidity, had an 8% rate of transient morbidity and achieved tumor volume reduction above 95% in 75% of selected cases, with 4 additional gross total resections. Second-look surgery is safe and effective with regard to volumetric outcome parameters even in cases with good initial resections, although the role of second-look surgery regarding oncological outcome has to be further investigated in times of personalized molecular medicine., (© 2022 The Authors.)
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- 2022
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28. Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood.
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Michler P, Schedel A, Witschas M, Friedrich UA, Wagener R, Mehtonen J, Brozou T, Menzel M, Walter C, Nabi D, Pearce G, Erlacher M, Göhring G, Dugas M, Heinäniemi M, Borkhardt A, Stölzel F, Hauer J, and Auer F
- Subjects
- Adult, DNA Damage genetics, Germ Cells, Germ-Line Mutation genetics, HEK293 Cells, Humans, Myeloid Cells, RNA, Messenger genetics, Telomere genetics, Young Adult, Genetic Predisposition to Disease genetics, Leukemia, Myeloid, Acute genetics, Myeloproliferative Disorders genetics, Shelterin Complex genetics, Telomere-Binding Proteins genetics
- Abstract
While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene POT1 , which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated POT1 display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional POT1 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisposition to myeloid malignancies in childhood.
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- 2021
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29. Increasing incidence and survival of paediatric and adolescent thyroid cancer in Cyprus 1998-2017: A population-based study from the Cyprus Pediatric Oncology Registry.
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Loizou L, Demetriou A, Erdmann F, Borkhardt A, Brozou T, Sharp L, and McNally R
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- Adolescent, Child, Cyprus epidemiology, Female, Humans, Incidence, Male, Registries, Thyroid Cancer, Papillary, Thyroid Neoplasms epidemiology
- Abstract
Background: Paediatric and adolescent thyroid cancer incidence rates are increasing in many countries. We determined incidence rates, temporal trends and survival from thyroid cancer diagnosed in childhood and adolescence in Cyprus during 1998-2017., Methods: Patients aged 0-19 years, diagnosed with thyroid cancer in the Pediatric Oncology Registry of Cyprus were included. Crude incidence rates, age standardized rates, time trends and overall survival were analysed. Annual rates and temporal trends were calculated using Microsoft Excel 2016 and Joinpoint regression analysis., Results: Eighty-one cases (76.5 % female, 23.5 % male) were identified. The crude rates (per 100,000 persons) were for both sexes 2.00 (95 % CI 1.61, 2.49), females 3.15 (95 % CI 2.45, 4.03) and males 0.92 (95 % CI 0.58, 1.44). The annual percentage changes of crude and standardised rates were 7.5 % (p < 0.05) and 7.6 % (p < 0.05). The annual percentage changes of crude rates were for females 5.1 % (p = 0.1), males 8.4 % (p < 0.05) and 15-19-year-olds 7.6 % (p < 0.05). The female to male rate ratio was 3.42 (95 % CI 2.06, 5.74). Papillary thyroid carcinoma represented 86.4 % of all cases. There was only one case after previous cancer therapy. The rate ratio of 2nd (2008-2017) to 1st (1998-2007) periods for metastatic (regional) stages was 3.76 (95 % CI 1.74, 8.31). Survival until 2018 was 100 %., Conclusion: This population-based study demonstrated that thyroid cancer incidence rates in 0-19-year-olds in Cyprus was among the world's highest. Increasing trends mainly affected males and females aged 15-19 years with papillary thyroid carcinoma, the dominant type. Cases after previous cancer therapy didn't contribute to increasing rates. The increase of metastatic cases suggests a true increase of thyroid cancer rather than overdiagnosis. Although prognosis is excellent with 100 % survival, the rising incidence rate is unexplained, indicating the need to identify causes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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30. Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer.
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Wagener R, Taeubner J, Walter C, Yasin L, Alzoubi D, Bartenhagen C, Attarbaschi A, Classen CF, Kontny U, Hauer J, Fischer U, Dugas M, Kuhlen M, Borkhardt A, and Brozou T
- Subjects
- Adolescent, Child, Female, Genetic Testing statistics & numerical data, Humans, Male, Neoplasms diagnosis, Exome Sequencing statistics & numerical data, Germ-Line Mutation, Neoplasms genetics, Phenotype
- Abstract
In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. We identified in 11/160 patients a pathogenic germline variant predisposing to cancer and a further eleven patients carried a prioritized VUS with a strong association to the cancerogenesis of the patient. Through clinical screening, 51 patients (31.3%) were identified as suspicious for an underlying cancer predisposition syndrome (CPS), but only in ten of those patients a pathogenic variant could be identified. In contrast, one patient with a classical CPS and ten patients with prioritized VUS were classified as unremarkable in the clinical work-up. Taken together, a monogenetic causative variant was detected in 13.8% of our patients using WES. Nevertheless, the still unclarified clinical suspicious cases emphasize the need to consider other genetic mechanisms including new target genes, structural variants, or polygenic interactions not previously associated with cancer predisposition., (© 2021. The Author(s).)
- Published
- 2021
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31. Supratentorial ependymoma in childhood: more than just RELA or YAP.
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Zschernack V, Jünger ST, Mynarek M, Rutkowski S, Garre ML, Ebinger M, Neu M, Faber J, Erdlenbruch B, Claviez A, Bielack S, Brozou T, Frühwald MC, Dörner E, Dreschmann V, Stock A, Solymosi L, Hench J, Frank S, Vokuhl C, Waha A, Andreiuolo F, and Pietsch T
- Subjects
- Adaptor Proteins, Signal Transducing, Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Transcription Factor RelA, Transcription Factors, YAP-Signaling Proteins, Ependymoma genetics, Ependymoma pathology, Supratentorial Neoplasms genetics, Supratentorial Neoplasms pathology
- Abstract
Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.
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- 2021
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32. QRICH1 variants in Ververi-Brady syndrome-delineation of the genotypic and phenotypic spectrum.
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Föhrenbach M, Jamra RA, Borkhardt A, Brozou T, Muschke P, Popp B, Rey LK, Schaper J, Surowy H, Zenker M, Zweier C, Wieczorek D, and Redler S
- Subjects
- Adolescent, Child, Child, Preschool, Codon, Nonsense genetics, Developmental Disabilities diagnostic imaging, Developmental Disabilities pathology, Exome genetics, Female, Frameshift Mutation genetics, Genotype, Humans, Intellectual Disability diagnostic imaging, Intellectual Disability pathology, Loss of Function Mutation genetics, Male, Mutation, Missense genetics, Phenotype, DNA-Binding Proteins genetics, Developmental Disabilities genetics, Genetic Predisposition to Disease, Intellectual Disability genetics, Transcription Factors genetics
- Abstract
Ververi-Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss-of-function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832_833del; p.(Ser278Leufs*25), c.1812_1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
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- 2021
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33. Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment.
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Hrusak O, Kalina T, Wolf J, Balduzzi A, Provenzi M, Rizzari C, Rives S, Del Pozo Carlavilla M, Alonso MEV, Domínguez-Pinilla N, Bourquin JP, Schmiegelow K, Attarbaschi A, Grillner P, Mellgren K, van der Werff Ten Bosch J, Pieters R, Brozou T, Borkhardt A, Escherich G, Lauten M, Stanulla M, Smith O, Yeoh AEJ, Elitzur S, Vora A, Li CK, Ariffin H, Kolenova A, Dallapozza L, Farah R, Lazic J, Manabe A, Styczynski J, Kovacs G, Ottoffy G, Felice MS, Buldini B, Conter V, Stary J, and Schrappe M
- Subjects
- Adolescent, COVID-19, Child, Coronavirus Infections drug therapy, Female, Humans, Male, Neoplasms complications, Pandemics, Pneumonia, Viral drug therapy, SARS-CoV-2, Surveys and Questionnaires, COVID-19 Drug Treatment, Antineoplastic Agents therapeutic use, Betacoronavirus, Coronavirus Infections complications, Neoplasms drug therapy, Pneumonia, Viral complications
- Abstract
Introduction: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia., Aim and Methods: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey., Results: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19., Conclusion: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment., Competing Interests: Conflict of interest statement The authors have no conflict of interest with regard to this study., (Copyright © 2020. Published by Elsevier Ltd.)
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- 2020
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34. Family-based germline sequencing in children with cancer.
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Kuhlen M, Taeubner J, Brozou T, Wieczorek D, Siebert R, and Borkhardt A
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- BRCA1 Protein genetics, Child, Family, Humans, Neoplasms diagnosis, Tumor Suppressor Protein p53 genetics, Genetic Predisposition to Disease, Germ-Line Mutation genetics, High-Throughput Nucleotide Sequencing trends, Neoplasms genetics
- Abstract
The discovery of cancer-predisposing syndromes (CPSs) using next-generation sequencing (NGS) technologies is of increasing importance in pediatric oncology with regard to diagnosis, treatment, surveillance, family counselling and research. Recent studies indicate that a considerable percentage of childhood cancers are associated with CPSs. However, the ratio of CPSs that are caused by inherited vs. de novo mutations (DNMs), the risk of recurrence, and even the total number of genes, which should be considered as a true cancer-predisposing gene, are still unknown. In contrast to sequencing only single index patients, family-based NGS of the germline is a very powerful tool for providing unique insights into inheritance patterns (e.g., DNMs, parental mosaicism) and types of aberrations (e.g., SNV, CNV, indels, SV). Furthermore, functional perturbations of key cancer pathways (e.g., TP53, FA/BRCA) by at least two co-inherited heterozygous digenic mutations from each parent and currently unrecognized rare variants and unmeasured genetic interactions between common and rare variants may be a widespread genetic phenomenon in the germline of affected children. Therefore, family-based trio sequencing has the potential to reveal a striking new landscape of inheritance in childhood cancer and to facilitate the integration and efforts of individualized treatment strategies, including personalized and preventive medicine and cancer surveillance programs. Consequently, cancer genetics is becoming an increasingly common approach in modern oncology, so trio-sequencing should also be routinely integrated into pediatric oncology.
- Published
- 2019
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35. Penetrance and Expressivity in Inherited Cancer Predisposing Syndromes.
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Taeubner J, Wieczorek D, Yasin L, Brozou T, Borkhardt A, and Kuhlen M
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- Genetic Variation, Humans, Penetrance, Risk Factors, Syndrome, Genetic Predisposition to Disease, Neoplasms genetics
- Abstract
Inherited diseases are not always expressed in the same way in every individual that carries the same variant in a disease-causing gene. This phenomenon is known as reduced or incomplete penetrance. Variable and incomplete penetrance may explain why inherited diseases are occasionally transmitted through unaffected parents, but also why clinically healthy individuals can carry potentially pathogenic variants without expressing features of the disease. Here, we will provide an overview of factors that play a fundamental role in the concept of penetrance and expressivity of cancer predisposing genes in children with malignancies. These findings are important to understand the complexity of inherited diseases and cancer development and to improve genetic counselling for the affected families., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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36. Diagnostic challenges in a child with early onset desmoplastic medulloblastoma and homozygous variants in MSH2 and MSH6.
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Taeubner J, Wimmer K, Muleris M, Lascols O, Colas C, Fauth C, Brozou T, Felsberg J, Riemer J, Gombert M, Ginzel S, Hoell JI, Borkhardt A, and Kuhlen M
- Subjects
- Cell Line, Tumor, Cells, Cultured, Cerebellar Neoplasms pathology, DNA-Binding Proteins metabolism, Diagnosis, Differential, Female, Homozygote, Humans, Infant, Medulloblastoma pathology, MutS Homolog 2 Protein metabolism, Cerebellar Neoplasms genetics, DNA-Binding Proteins genetics, Genetic Testing methods, Medulloblastoma genetics, MutS Homolog 2 Protein genetics, Phenotype
- Abstract
Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer susceptibility syndrome caused by biallelic germline mutations in one of the mismatch repair (MMR) genes. The spectrum of CMMRD-associated tumours is very broad and many CMMRD patients additionally display signposting non-neoplastic features, most frequently café-au-lait macules and other pigmentation alterations. We report on a 13-month-old girl suspected of having CMMRD due to a desmoplastic medulloblastoma and a striking skin pigmentation that included multiple café-au-lait macules, hypopigmented areas and Mongolian spots. Whole-exome sequencing revealed homozygosity for MSH2 variant p.(Leu92Val) and MSH6 variant p.(Val809del), both variants of uncertain significance (VUS). Immunohistochemical analysis of the tumour tissue showed expression of all four MMR proteins and gMSI testing was negative. However, functional assays demonstrated that the cells of the patient displayed methylation tolerance and ex vivo microsatellite instability, which unequivocally confirmed the diagnosis of CMMRD. Taken together, the results render the MSH2 variant unlikely to be responsible for the phenotype, while they are compatible with MSH6-associated CMMRD. This case illustrates the diagnostic strategy of confirming CMMRD syndrome in patients with VUS.
- Published
- 2018
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37. Correction to: Genetic predisposition in children with cancer - affected families' acceptance of Trio-WES.
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Brozou T, Taeubner J, Velleuer E, Dugas M, Wieczorek D, Borkhardt A, and Kuhlen M
- Abstract
The original version of this article, unfortunately, contained an error. The reference citations in the original paper are incorrectly cited to its corresponding bibliographic information. The original article was corrected.
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- 2018
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38. Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations.
- Author
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Taeubner J, Brozou T, Qin N, Bartl J, Ginzel S, Schaper J, Felsberg J, Fulda S, Vokuhl C, Borkhardt A, and Kuhlen M
- Subjects
- Humans, Infant, Newborn, Male, Rhabdomyosarcoma, Embryonal pathology, Germ-Line Mutation, Patched-1 Receptor genetics, Patched-2 Receptor genetics, Rhabdomyosarcoma, Embryonal genetics
- Abstract
The sonic hedgehog (SHH) signaling pathway has been shown to play important roles in embryogenesis, cell proliferation as well as in cell differentiation. It is aberrantly activated in various common cancers in adults, but also in pediatric neoplasms, such as rhabdomyosarcoma (RMS) and atypical teratoid/rhabdoid tumors (AT/RTs). Dysregulation and germline mutation in PATCHED1 (PTCH1), a receptor for SHH, is responsible for the Gorlin Syndrome, a familial cancer predisposing syndrome including RMS. Here, we report a newborn diagnosed with congenital embryonal RMS. Whole-exome sequencing (WES) identified the presence of two heterozygous germline mutations in two target genes of the SHH signaling pathway. The PTCH1 mutation p.(Gly38Glu) is inherited from the mother, whereas the PTCH2 p.(His622Tyr) mutation is transmitted from the father. Quantitative RT-PCR expression analysis of GLI and SMO, key players of the SHH pathway, showed significantly increase in the tumor tissue of the patient and also enrichment in the germline sample in comparison to the parents indicating activation of the SHH pathway in the patient. These findings demonstrate that SHH pathway activity seems to play a role in eRMS as evidenced by high expression levels of GLI1 RNA transcripts. We speculate that PTCH2 modulates tumorigenesis linked to the PTCH1 mutation and is likely associated with the congenital onset of the RMS observed in our patient.
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- 2018
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39. Genetic predisposition in children with cancer - affected families' acceptance of Trio-WES.
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Brozou T, Taeubner J, Velleuer E, Dugas M, Wieczorek D, Borkhardt A, and Kuhlen M
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- Adolescent, Adult, Child, Child, Preschool, Family, Female, Humans, Infant, Infant, Newborn, Informed Consent, Male, Middle Aged, Neoplastic Syndromes, Hereditary genetics, Prospective Studies, Young Adult, Attitude to Health, Genetic Predisposition to Disease, Genetic Testing methods, Neoplastic Syndromes, Hereditary diagnosis, Exome Sequencing
- Abstract
A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). The ratio of CPSs caused by inherited versus de novo germline mutations and the risk of recurrence in other children are unknown. We initiated a prospective study performing whole-exome sequencing (WES) of parent-child trios in children newly diagnosed with cancer. We initially aimed to determine the interest in and acceptance of trio WES among affected families and to systematically collect demographic, medical, and family history data to analyze whether these point to an underlying CPS. Between January 2015 and December 2016, 83 (88.3%) of 94 families participated; only 11 (11.7%) refused to participate. Five (6.0%) children presented with congenital malignancies and three (3.6%) with tumors with a high likelihood of an underlying CPS. Two (2.5%) families showed malignancies in family members < 18 years, 11 (13.8%) showed relatives < 45 years with cancer, 37 (46.3%) had a positive cancer history, and 14 (17.5%) families had > 1 relative with cancer., Conclusions: Genetic testing in pediatric oncology is of great interest to the families, and the vast majority opts for investigation into potentially underlying CPSs. Trio sequencing provides unique insights into CPS in pediatric cancers and is increasingly becoming a common approach in modern oncology, and thus, trio sequencing needs also to be integrated routinely into the practice of pediatric oncology. What is Known: • A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). What is New: • Knowing about an underlying CPS and, thus, the risk of recurrence in other children is of great interest to affected families.
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- 2018
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40. Embryonal rhabdomyosarcoma in a patient with a heterozygous frameshift variant in the DICER1 gene and additional manifestations of the DICER1 syndrome.
- Author
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Fremerey J, Balzer S, Brozou T, Schaper J, Borkhardt A, and Kuhlen M
- Subjects
- Brain Neoplasms genetics, Child, Female, Frameshift Mutation, Genetic Predisposition to Disease genetics, Heterozygote, Humans, Neuroectodermal Tumors, Primitive genetics, Pulmonary Blastoma genetics, DEAD-box RNA Helicases genetics, Neoplastic Syndromes, Hereditary genetics, Rhabdomyosarcoma, Embryonal genetics, Ribonuclease III genetics, Urinary Bladder Neoplasms genetics
- Abstract
Germline mutations in the DICER1 gene are associated with an inherited cancer predisposition syndrome also known as the DICER1-syndrome, which is implicated in a broad range of tumors including pleuropulmonary blastoma, ovarian Sertoli-Leydig cell tumors, ciliary body medulloepithelioma (CBME), pituitary blastoma, embryonal rhabdomyosarcoma (eRMS), anaplastic renal sarcoma as well as ocular, sinonasal tumors ovarian sex-cord tumors, thyroid neoplasia and cystic nephroma. This study describes a novel, heterozygous frameshift DICER1 mutation in a patient, who is affected by different tumors of the DICER1-syndrome, including eRMS, CBME and suspected pleuropulmonary blastoma type I. By whole-exome sequencing of germline material using peripheral blood-derived DNA, we identified a single base pair duplication within the DICER1 gene (c.3405 dupA) that leads to a frameshift and results in a premature stop in exon 21 (p.Gly1136Arg). The metachronous occurrence of two unrelated tumor entities (eRMS and CBME) in a very young child within a short timeframe should have raised the suspicion of an underlying cancer susceptibility syndrome and should be prompt tested for DICER1.
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- 2017
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41. Acalculous cholecystitis or biliary dyskinesia for Epstein-Barr virus gallbladder involvement?
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Fretzayas A, Moustaki M, Attilakos A, Brozou T, and Nicolaidou P
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- Acalculous Cholecystitis diagnostic imaging, Biliary Dyskinesia diagnostic imaging, Child, Female, Humans, Radionuclide Imaging, Ultrasonography, Acalculous Cholecystitis virology, Biliary Dyskinesia virology, Infectious Mononucleosis complications
- Abstract
We present two patients with Epstein-Barr virus (EBV) infection related to gallbladder involvement. Such an association is already known as EBV induced acalculous cholecystitis, diagnosed on the basis of ultrasonographic findings. In our patients, radioisotopic cholescintigraphy was also performed and it showed that gallbladder was visualized in both patients in contrast to that what can be observed in cases of cholecystitis. However, the value of ejection fraction was compatible with biliary dyskinesia. We, therefore, consider that impaired gallbladder contractility in EBV infection cases may actually represent biliary dyskinesia and not acalculous cholecystitis taking into account the radioisotopic findings and the self limited course of the disorder.
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- 2014
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42. MRSA blistering distal dactylitis and review of reported cases.
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Fretzayas A, Moustaki M, Tsagris V, Brozou T, and Nicolaidou P
- Subjects
- Anti-Bacterial Agents therapeutic use, Blister drug therapy, Blister microbiology, Community-Acquired Infections diagnosis, Community-Acquired Infections drug therapy, Community-Acquired Infections microbiology, Drainage, Female, Hand Dermatoses drug therapy, Humans, Infant, Methicillin-Resistant Staphylococcus aureus drug effects, Staphylococcal Skin Infections drug therapy, Staphylococcal Skin Infections microbiology, Treatment Outcome, Vancomycin therapeutic use, Blister diagnosis, Fingers microbiology, Hand Dermatoses microbiology, Methicillin-Resistant Staphylococcus aureus isolation & purification, Staphylococcal Skin Infections diagnosis
- Abstract
We describe a 6-month-old infant with blistering distal dactylitis. Bacterial culture from the skin lesion grew methicillin resistant Staphylococcus aureus. No carriage of this bacterial agent was identified in her family. She responded to vancomycin administration and incision and drainage of the lesion. This is the first reported case of methicillin resistant Staphylococcus aureus-associated blistering distal dactylitis in an infant., (© 2011 Wiley Periodicals, Inc.)
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- 2011
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