Publications by authors named "David Sumerauer"

40 Publications

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

J Clin Oncol 2021 May 4:JCO2002636. Epub 2021 May 4.

Lebanese American University Medical Center-Rizk, Beirut, Lebanon.

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals.

Patients And Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation.

Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years.

Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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http://dx.doi.org/10.1200/JCO.20.02636DOI Listing
May 2021

Atypical Teratoid/Rhabdoid Tumor (AT/RT) With Molecular Features of Pleomorphic Xanthoastrocytoma.

Am J Surg Pathol 2021 Feb 24. Epub 2021 Feb 24.

*Institute of Neuropathology **Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster †Hopp Children's Cancer Center (KiTZ) ‡Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg §Institute of Human Genetics, University of Ulm & Ulm University Hospital, Ulm ∥Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg ¶Swabian Childrens' Cancer Center, University Childrens' Hospital Augsburg and EU-RHAB Registry, Augsburg #Department of Neuropathology, Institute of Pathology, Hannover Medical School ‡‡Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany ††Department of Pediatric Hematology and Oncology, University Hospital Motol, Charles University, 2nd Medical School, Prague, Czech Republic §§Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18 y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences.
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http://dx.doi.org/10.1097/PAS.0000000000001694DOI Listing
February 2021

Older age is a protective factor for academic achievements irrespective of treatment modalities for posterior fossa brain tumours in children.

PLoS One 2020 16;15(12):e0243998. Epub 2020 Dec 16.

Department of Radiology, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

The treatment of children with posterior fossa brain tumours (PFBT) impacts their long term functional and imaging outcomes. This study aimed to evaluate academic achievement correlated with long-term sequelae after different PFBT treatment modalities. The study cohort consisted of 110 survivors (median age at diagnosis 10.1 years and median time of follow up 13.2 years) who completed hearing questionnaires, neurological assessment and MRI of the brain ≥5 years after the end of treatment. There were three treatment groups. A cisplatin group which underwent cisplatin chemotherapy, radiotherapy and surgery (medulloblastoma N = 40), a radiotherapy group which underwent radiotherapy and surgery (astrocytoma/ependymoma N = 30), and a surgery group (astrocytoma N = 40). Academic achievement was correlated to the age at diagnosis, ototoxicity, Karnofsky score (KS), and MRI findings (Fazekas Score (FS)- treatment related parenchymal changes). For a modelled age at diagnosis of five years, the cisplatin group had lower academic achievements compared to the radiotherapy (p = 0.028) and surgery (p = 0.014) groups. Academic achievements evaluated at a modelled age of 10 years at diagnosis did not significantly differ among the treatment groups. The cisplatin group exhibited a higher occurrence of ototoxicity than the radiotherapy (p<0.019) and surgery groups (p<0.001); however, there was no correlation between ototoxicity and academic achievements (p = 0.722) in older age at diagnosis. The radiotherapy group exhibited lower KS than the surgery group (p<0.001). KS significantly influenced academic achievements in all groups (p<0.000). The cisplatin group exhibited higher FS than the surgery group (p<0.001) while FS did not correlate with academic achievement (p = 0.399). Older age is a protective factor for academic achievements irrespective of a treatment modality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243998PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743944PMC
February 2021

Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.

Cell 2020 12 30;183(6):1617-1633.e22. Epub 2020 Nov 30.

Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
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http://dx.doi.org/10.1016/j.cell.2020.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791404PMC
December 2020

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

JCO Precis Oncol 2020 20;4. Epub 2020 May 20.

Semmelweis University, Budapest, Hungary.

Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors.

Patients And Methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries.

Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( = .02).

Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.
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http://dx.doi.org/10.1200/PO.19.00298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446502PMC
May 2020

Bevacizumab for pediatric radiation necrosis.

Neurooncol Pract 2020 Jul 20;7(4):409-414. Epub 2020 Jan 20.

Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.

Background: Radiation necrosis is a frequent complication occurring after the treatment of pediatric brain tumors; however, treatment options remain a challenge. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown in small adult cohorts to confer a benefit, specifically a reduction in steroid usage, but its use in children has not been well described.

Methods: We describe our experience with bevacizumab use for symptomatic radiation necrosis at 5 institutions including patients treated after both initial irradiation and reirradiation.

Results: We identified 26 patients treated with bevacizumab for symptomatic radiation necrosis, with a wide range of underlying diagnoses. The average age at diagnosis of radiation necrosis was 10.7 years, with a median time between the last dose of radiation and the presentation of radiation necrosis of 3.8 months (range, 0.6-110 months). Overall, we observed that 13 of 26 patients (50%) had an objective clinical improvement, with only 1 patient suffering from significant hypertension. Radiological improvement, defined as reduced T2/fluid-attenuated inversion recovery signal and mass effect, was observed in 50% of patients; however, this did not completely overlap with clinical response. Both early and late radiation necrosis responded equally well to bevacizumab therapy. Overall, bevacizumab was very well tolerated, permitting a reduction of corticosteroid dose and/or duration in the majority of patients.

Conclusions: Bevacizumab appears to be effective and well-tolerated in children as treatment for symptomatic radiation necrosis and warrants more robust study in the context of controlled clinical trials.
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http://dx.doi.org/10.1093/nop/npz072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393279PMC
July 2020

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Cell Rep Med 2020 Jun;1(3)

Departments of Pediatrics, Anatomy, and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA.

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
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http://dx.doi.org/10.1016/j.xcrm.2020.100038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394286PMC
June 2020

Plerixafor combined with standard regimens for hematopoietic stem cell mobilization in pediatric patients with solid tumors eligible for autologous transplants: two-arm phase I/II study (MOZAIC).

Bone Marrow Transplant 2020 09 3;55(9):1744-1753. Epub 2020 Mar 3.

IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

This study (NCT01288573) investigated plerixafor's safety and efficacy in children with cancer. Stage 1 investigated the dosage, pharmacokinetics (PK), pharmacodynamics (PD), and safety of plerixafor + standard mobilization (G-CSF ± chemotherapy). The stage 2 primary endpoint was successful mobilization (doubling of peripheral blood CD34+ cell count in the 24 h prior to first apheresis) in patients treated with plerixafor + standard mobilization vs. standard mobilization alone. In stage 1, three patients per age group (2-<6, 6-<12, and 12-<18 years) were treated at each dose level (160, 240, and 320 µg/kg). Based on PK and PD data, the dose proposed for stage 2 was 240 µg/kg (patients 1-<18 years), in which 45 patients were enrolled (30 plerixafor arm, 15 standard arm). Patient demographics and characteristics were well balanced across treatment arms. More patients in the plerixafor arm (24/30, 80%) met the primary endpoint of successful mobilization than in the standard arm (4/14, 28.6%, p = 0.0019). Adverse events reported as related to study treatment were mild, and no new safety concerns were identified. Plerixafor + standard G-CSF ± chemotherapy mobilization was generally well tolerated and efficacious when used to mobilize CD34+ cells in pediatric cancer patients.
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http://dx.doi.org/10.1038/s41409-020-0836-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452813PMC
September 2020

Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors.

Neuro Oncol 2020 07;22(7):1006-1017

Department of Pediatric Hematology and Oncology, University of Würzburg, Würzburg, Germany.

Background: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses.

Methods: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors.

Results: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%).

Conclusions: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.
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http://dx.doi.org/10.1093/neuonc/noz244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339901PMC
July 2020

The molecular landscape of ETMR at diagnosis and relapse.

Nature 2019 12 4;576(7786):274-280. Epub 2019 Dec 4.

Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.
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http://dx.doi.org/10.1038/s41586-019-1815-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908757PMC
December 2019

Spinal cord atypical teratoid/rhabdoid tumors in children: Clinical, genetic, and outcome characteristics in a representative European cohort.

Pediatr Blood Cancer 2020 01 1;67(1):e28022. Epub 2019 Oct 1.

Swabian Children's Cancer Center, University Children's Hospital, University Hospital Augsburg, Augsburg, Germany.

Background: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT.

Methods: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3).

Results: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation.

Conclusions: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.
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http://dx.doi.org/10.1002/pbc.28022DOI Listing
January 2020

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Nat Commun 2019 09 25;10(1):4343. Epub 2019 Sep 25.

Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-019-12187-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761184PMC
September 2019

Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

J Neurooncol 2019 Oct 14;145(1):177-184. Epub 2019 Sep 14.

Hospital de Pediatría, Centro Médico National Siglo XXI, Instituto Mexicano del Seguro Social, Jefatura de Servicio de Oncologia, Distrito Federal, Mexico.

Introduction: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines.

Methods: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively.

Results: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials.

Conclusion: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.
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http://dx.doi.org/10.1007/s11060-019-03287-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775536PMC
October 2019

Brain gliomas, hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1.

Brain Dev 2019 Sep 15;41(8):678-690. Epub 2019 Apr 15.

Department of Neurosurgery, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.

Purpose: To evaluate the incidence and clinical importance of brain gliomas - optic pathway gliomas (OPGs) and especially gliomas outside the optic pathway (GOOP) for children with neurofibromatosis type 1 (NF1), additionally, to assess the causes of obstructive hydrocephalus in NF1 children with an emphasis on cases caused by idiopathic aqueduct stenosis.

Subjects And Methods: We analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery.

Results: We have found OPGs in 77/285 (27%) children and GOOPs in 29/285 (10,2%) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30,5%). GOOPs were significantly more often treated than OPGs (p > 0.01). OPGs contain clinically important subgroup of 14/285 (4.9%) spreading to hypothalamus. Spontaneous regression was documented in 4/285 (1.4%) gliomas and the same number of NF1 children died due to gliomas. Obstructive hydrocephalus was found in 22/285 (7.7%) patients and 14/22 cases were due to glioma. Idiopathic aqueduct stenosis caused hydrocephalus in 6/22 cases and was found in 2.1% of NF1 children. Two had other cause.

Conclusions: The total brain glioma number (OPGs and only GOOPs together) better reflected the overall brain tumour risk for NF1 children. However, GOOPs occur less frequently than OPGs, they are more clinically relevant. The obstructive hydrocephalus was severe and featuring frequent complication, especially those with GOOP. Idiopathic aqueduct stenosis shows an unpredictable cause of hydrocephalus in comparison with glioma and is another reason for careful neurologic follow up.
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http://dx.doi.org/10.1016/j.braindev.2019.04.003DOI Listing
September 2019

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue.

J Clin Oncol 2019 02 4;37(6):461-470. Epub 2019 Jan 4.

23 Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Purpose: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD.

Patients And Methods: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome.

Results: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days.

Conclusion: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
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http://dx.doi.org/10.1200/JCO.18.00474DOI Listing
February 2019

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

Lancet Oncol 2018 06 9;19(6):785-798. Epub 2018 May 9.

Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.

Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MB), SHH (MB), group 3 (MB), and group 4 (MB). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.

Findings: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MB subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MB subgroup). Patients with germline APC mutations developed MB and accounted for most (five [71%] of seven) cases of MB that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MB. Germline TP53 mutations presented only in childhood patients in the MB subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MB, MB, and MB molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.

Interpretation: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MB and MB because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.

Funding: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.
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http://dx.doi.org/10.1016/S1470-2045(18)30242-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984248PMC
June 2018

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.

Cell 2018 02;172(5):1050-1062.e14

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Toronto General Research Institute, University Health Network, Toronto, ON, Canada.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.
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http://dx.doi.org/10.1016/j.cell.2018.01.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346737PMC
February 2018

Differential patterns of metastatic dissemination across medulloblastoma subgroups.

J Neurosurg Pediatr 2018 02 8;21(2):145-152. Epub 2017 Dec 8.

1Department of Paediatrics, Division of Haematology/Oncology.

OBJECTIVE Metastatic dissemination is a major treatment challenge and cause of death in patients with medulloblastoma. However, the influence of molecular biology on the pattern of metastatic dissemination at diagnosis is not known. In this study, the authors sought to define the location, pattern, and imaging characteristics of medulloblastoma metastases across subgroups at diagnosis. METHODS A consecutive cohort of patients with metastatic medulloblastoma at The Hospital for Sick Children and the University Hospital Motol, who underwent up-front MRI of the craniospinal axis, was assembled and allocated to subgroups using NanoString limited gene-expression profiling. Radiological characteristics (including location, morphology, size, diffusion restriction, and contrast enhancement) were discerned through a retrospective review. RESULTS Forty metastatic medulloblastomas were identified with up-front neuroimaging of the craniospinal axis: 5 sonic hedgehog (SHH), 16 Group 3, and 19 Group 4 metastases. Significant subgroup-specific differences were observed, particularly with respect to tumor location, size, and morphology. Group 3 metastases were most frequently laminar compared with a more nodular pattern in Group 4 (14 of 16 in Group 3 vs 8 of 19 in Group 4; p = 0.0004). Laminar metastases were not observed in patients with SHH medulloblastoma. Suprasellar metastases are highly specific to Group 4 (p = 0.016). Two of the 5 SHH cases had multifocal lesions in the cerebellum, raising the possibility that these were in fact synchronous primary tumors and not true metastases. A minority of patients with Group 4 metastases harbored metastatic deposits that did not enhance on MRI after contrast administration, often in patients whose primary tumor did not enhance. CONCLUSIONS The location, morphology, and imaging characteristics of metastatic medulloblastoma differ across molecular subgroups, with implications for diagnosis and management. This suggests that the biology of leptomeningeal dissemination differs among medulloblastoma subgroups.
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http://dx.doi.org/10.3171/2017.8.PEDS17264DOI Listing
February 2018

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas.

J Clin Oncol 2017 Sep 20;35(25):2934-2941. Epub 2017 Jul 20.

Alvaro Lassaletta, Michal Zapotocky, Matthew Mistry, Vijay Ramaswamy, Marion Honnorat, Rahul Krishnatry, Ana Guerreiro Stucklin, Nataliya Zhukova, Anthony Arnoldo, Scott Ryall, Catriona Ling, Tara McKeown, Jim Loukides, James T. Rutka, Peter Dirks, Michael D. Taylor, Shiyi Chen, Ute Bartels, Annie Huang, Eric Bouffet, Cynthia Hawkins, and Uri Tabori, The Hospital for Sick Children, Toronto; Adam Fleming, McMaster Children's Hospital, McMaster University, Hamilton; Shayna Zelcer, Children's Hospital of Western Ontario, London, Ontario; David Eisenstat and Bev Wilson, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta; Anne Sophie Carret, Hospital Sainte Justine; Nada Jabado, McGill University, Montreal; Valerie Larouche, Centre Hospitalier Universitaire de Québec, Québec City, Quebec, Canada; Ofelia Cruz and Carmen de Torres, Hospital Sant Joan de Déu, Barcelona, Spain; Cheng-Ying Ho, University of Maryland School of Medicine, Baltimore, MD; Roger J. Packer, Children's National Health System, Washington, DC; Ruth Tatevossian, Ibrahim Qaddoumi, Julie H. Harreld, James D. Dalton, and David W. Ellison, St Jude Children's Research Hospital, Memphis, TN; Jean Mulcahy-Levy and Nicholas Foreman, Children's Hospital Colorado, Aurora, CO; Matthias A. Karajannis, Shiyang Wang, and Matija Snuderl, New York University Langone Medical Center, New York, NY; Amulya Nageswara Rao and Caterina Giannini, The Mayo Clinic, Rochester, MN; Mark Kieran and Keith L. Ligon, Dana-Farber Cancer Institute, Boston Children's Hospital, Boston, MA; Maria Luisa Garre, Paolo Nozza, Samantha Mascelli, and Alessandro Raso, Istituto Giannina Gaslini, Genoa, Italy; Sabine Mueller and Theodore Nicolaides, University of California, San Francisco, San Francisco, CA; Karen Silva and Romain Perbet, Hospices Civils de Lyon; Alexandre Vasiljevic, Cécile Faure Conter, and Didier Frappaz, Institute of Pediatric Hematology and Oncology, Lyon, France; Sarah Leary and Courtney Crane, Seattle Children's Hospital, Seattle, WA; Aden Chan and Ho-Keung Ng, The Chinese University of Hong Kong, Hong Kong; Zhi-Feng Shi and Ying Mao, Huashan Hospital, Fudan University, Shanghai, People's Republic of China; Elizabeth Finch, University of North Carolina, School of Medicine, Chapel Hill, NC; Peter Hauser, Semmelweis University, Budapest, Hungary; and David Sumerauer and Lenka Krskova, University Hospital Motol, Charles University, 2nd Medical School, Prague, Czech Republic.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.
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http://dx.doi.org/10.1200/JCO.2016.71.8726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791837PMC
September 2017

Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease.

J Neurooncol 2017 04 21;132(2):255-266. Epub 2017 Jan 21.

Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.
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http://dx.doi.org/10.1007/s11060-016-2363-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378734PMC
April 2017

Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable long-term outcome.

Brain Pathol 2017 07 11;27(4):411-418. Epub 2016 Aug 11.

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Rhabdoid phenotype and loss of SMARCB1 expression in a brain tumor are characteristic features of atypical teratoid/rhabdoid tumors (ATRT). Rare non-rhabdoid brain tumors showing cribriform growth pattern and SMARCB1 loss have been designated cribriform neuroepithelial tumor (CRINET). Small case series suggest that CRINETs may have a relatively favorable prognosis. However, the long-term outcome is unclear and it remains uncertain whether CRINET represents a distinct entity or a variant of ATRT. Therefore, 10 CRINETs were clinically and molecularly characterized and compared with 10 ATRTs of each of three recently described molecular subgroups (i.e. ATRT-TYR, ATRT-SHH and ATRT-MYC) using Illumina Infinium HumanMethylation450 arrays, FISH, MLPA, and sequencing. Furthermore, outcome was compared to a larger cohort of 27 children with ATRT-TYR. Median age of the 6 boys and 4 girls harboring a CRINET was 20 months. On histopathological examination, all CRINETs demonstrated a cribriform growth pattern and distinct tyrosinase staining. On unsupervised cluster analysis of methylation data, all CRINETs examined exclusively clustered within the ATRT-TYR molecular subgroup. As ATRT-TYR, CRINETs mainly showed large heterozygous 22q deletions (9/10) and SMARCB1 mutations of the other allele. In two patients, SMARCB1 mutations were also present in the germline. Estimated mean overall survival in patients with CRINETs was 125 months (95% confidence interval 100-151 months) as compared to only 53 (33-74) months in patients with ATRTs of the ATRT-TYR subgroup (Log-Rank P < 0.05). In conclusion, CRINET represents a SMARCB1-deficient non-rhabdoid tumor, which shares molecular similarities with the ATRT-TYR subgroup but has distinct histopathological features and favorable long-term outcome.
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http://dx.doi.org/10.1111/bpa.12413DOI Listing
July 2017

Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes.

Cancer Cell 2016 Mar 25;29(3):379-393. Epub 2016 Feb 25.

Department of Neuropathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, 69120 Heidelberg, Germany.

Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
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http://dx.doi.org/10.1016/j.ccell.2016.02.001DOI Listing
March 2016

Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children.

Eur J Med Genet 2016 Mar 2;59(3):152-7. Epub 2015 Dec 2.

Department of Pediatric Hematology and Oncology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare genetic disorder characterized by early onset of childhood malignancies, including acute leukemia, brain cancer and nephroblastoma. Here, we present a case report of a family with 3 affected children in terms of treatment outcome, toxicity and characterization of the malignancies using comprehensive cytogenetic analysis. The first child was diagnosed with T-cell acute lymphoblastic leukemia when he was 11 months old. During chemotherapy, he suffered from repeated pancytopenia, sepsis and severe vincristine polyneuropathy, and 18 months after primary diagnosis, he succumbed to secondary acute monocytic leukemia. The second child was diagnosed with stage 2 triphasic nephroblastoma (Wilms tumor), when he was 3 years and 11 months old. During chemotherapy, he suffered from vincristine polyneuropathy. Currently, he is in complete remission, 29 months following the initial diagnosis. The third child was diagnosed with medulloblastoma with classical histology, when she was 4 years and 5 months old. After the first cycle of chemotherapy, she suffered from prolonged pancytopenia, sepsis and severe skin and mucosal toxicity. Six weeks after primary diagnosis, a first relapse in the posterior fossa was diagnosed, and at 7 and half months after primary diagnosis, a second relapse was diagnosed that led to the patient's death. Our case report underscores tumor heterogeneity, treatment toxicity and poor outcome in Fanconi anemia patients of complementation group D1.
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http://dx.doi.org/10.1016/j.ejmg.2015.11.013DOI Listing
March 2016

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.

Nature 2014 Jul 22;511(7510):428-34. Epub 2014 Jun 22.

Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.

Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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http://dx.doi.org/10.1038/nature13379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201514PMC
July 2014

Clinical and genetic features of rhabdoid tumors of the heart registered with the European Rhabdoid Registry (EU-RHAB).

Cancer Genet 2014 Sep 21;207(9):379-83. Epub 2014 Apr 21.

Children's Hospital Augsburg, Swabian Children's Cancer Center, Augsburg, Germany; Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Germany. Electronic address:

Rhabdoid tumors are rare but highly aggressive malignancies of infancy and early childhood with a generally unfavorable prognosis. Despite a wide variety of anatomic locations rhabdoid tumors share mutational inactivation of the SWI/SNF (SWItch/Sucrose NonFermentable) core component gene SMARCB1 (also known as INI1, hSNF5 or BAF47) in chromosome 22. As this inactivation usually results in loss of SMARCB1 expression, detectable by an antibody against the SMARCB1 protein, the accurate diagnosis of a rhabdoid tumor may be more distinctly and frequently made. Several reports on rhabdoid tumors presenting in various anatomic sites outside the kidneys and CNS are on record. We report two cases of rhabdoid tumors originating in the heart (cardiac tissue), which were entered into the European Rhabdoid Registry (EU-RHAB). The first case presented with intracardial and -cranial lesions as well as malignant ascites, while the second patient demonstrated an isolated cardiac tumor. This induced a different therapeutic approach and subsequently different clinical course (death 7 weeks after diagnosis in patient 1). Patient 2 presented with a bifocal intracardial tumor without metastases and remains in complete remission for 46 months since diagnosis following multimodal therapy. The second case demonstrates that even in a potentially futile clinical situation early and accurate diagnosis followed by prompt and intensive multimodal therapy may offer prolonged survival, potential cure and improved quality of life.
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http://dx.doi.org/10.1016/j.cancergen.2014.04.005DOI Listing
September 2014

Skin lesions in a boy with X-linked lymphoproliferative disorder: comparison of 5 SH2D1A deletion cases.

Pediatrics 2012 Feb 23;129(2):e523-8. Epub 2012 Jan 23.

Department of Pediatric Hematology and Oncology, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.

SH2D1A gene defects are the cause of X-linked lymphoproliferative disorder (XLP-1), a rare condition characterized by severe immune dysregulation. We present a patient lacking the typical symptoms of XLP-1, but experiencing a severe unusual skin condition encompassing features of dermatosclerosis and vesiculobullous skin disease. A maternal cousin of the patient was diagnosed with XLP-1 and found to carry a deletion of the SH2D1A gene. SH2D1A deletion was also identified in our patient, which offered a possible explanation for his skin symptoms. Subsequent analysis showed that the deletion in both cousins was identical and involved the whole SH2D1A gene and a part of the adjacent ODZ1 gene. High phenotypic variability of XLP-1 observed in this family prompted us to analyze the genotype-phenotype correlation of 2 different-sized deletions involving SH2D1A and ODZ1 in 5 patients from 2 families, and we report the clinical and laboratory data on these individuals. Our findings illustrate the wide clinical variability of XLP-1, both inter- and intrafamilial, which may complicate the diagnosis of this condition. The comparison of phenotypes of our patients argues against a strong involvement of the ODZ1 gene in the skin disorder and other symptoms observed in our index patient. His hitherto not described severe skin condition extends the phenotypic range of XLP-1.
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http://dx.doi.org/10.1542/peds.2011-0870DOI Listing
February 2012

Molecular cytogenetic characterization in four pediatric pheochromocytomas and paragangliomas.

Pathol Oncol Res 2011 Dec 5;17(4):801-8. Epub 2011 Apr 5.

Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, Fakultní nemocnice v Motole, V uvalu 84, Prague 5- Motol, Czech Republic.

Pheochromocytomas (PCCs) are rare tumors among children and adolescents and therefore are not genetically well characterized. The most frequently observed chromosomal changes in PCC are losses of 1p, 3q and/or 3p, 6q, 17p, 11q, 22q, and gains of 9q and 17q. Aberrations involving chromosome 11 are more common in malignant tumors. Unfortunately information about gene aberrations in childhood PCC's is limited. We used comparative genomic hybridization (CGH) and array comparative genomic hybridization (aCGH) to screen for copy number changes in four children suffering from pheochromocytoma or paraganglioma. Patients were diagnosed at the age 13 or 14 years. Bilateral pheochromocytoma was associated with von Hippel-Lindau syndrome (VHL). Multiple paraganglioma was associated with a germline mutation in SDHB. We found very good concordance between the results of CGH and aCGH techniques. Losses were observed more frequently than gains. All cases had a loss of chromosome 11 or 11p. Other aberrations were loss of chromosome 3 and 11 in sporadic pheochromocytoma, and loss of 3p and 11p in pheochromocytoma, which carried the VHL mutation. The deletion of chromosome 1p and other changes were observed in paragangliomas. We conclude that both array CGH and CGH analysis identified similar chromosomal regions involved in tumorigenesis of pheochromocytoma and paragangliomas, but we found 3 discrepancies between the methods. We didn't find any, of the proposed, molecular markers of malignancy in our benign cases and therefore we speculate that molecular cytogenetic examination may be helpful in separating benign and malignant forms in the future.
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http://dx.doi.org/10.1007/s12253-011-9385-8DOI Listing
December 2011