Publications by authors named "Simone Hettmer"

60 Publications

Breast cancer characteristics and surgery among women with Li-Fraumeni syndrome in Germany-A retrospective cohort study.

Cancer Med 2021 Sep 26. Epub 2021 Sep 26.

Department of Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany.

Background: Women with Li-Fraumeni syndrome (LFS) have elevated breast cancer (BC) risk. Optimal BC treatment strategies in this population are yet unknown.

Methods: BC subtypes and treatment were retrospectively investigated between December 2016 and January 2019 in a multicentre study. BC risks were evaluated according to the type of surgery.

Results: Thirty-five women of our study population (35/44; 79.5%) had developed 36 breast lesions at first diagnosis at a mean age of 34 years. Those breast lesions comprised 32 invasive BCs (89%), three ductal carcinoma in situ alone (8%) and one malignant phyllodes tumour (3%). BCs were mainly high-grade (18/32), of no special type (NST; 31/32), HER2-enriched (11/32) or luminal-B-(like)-type (10/32). Affected women (n = 35) received breast-conserving surgery (BCS, n = 17) or a mastectomy (ME, n = 18) including seven women with simultaneous contralateral prophylactic mastectomy (CPM) at first diagnosis. Nineteen women suffered 20 breast or locoregional axillary lesions at second diagnosis with mean age of 36. Median time between first and second diagnosis was 57 months; median time to contra- and ipsilateral recurrence depended on surgical strategies (BCS: 46 vs. unilateral ME: 93 vs. bilateral ME > 140 months). Women with a primary treatment of solitaire therapeutic ME suffered from contralateral BC earlier compared to those with therapeutic ME and CPM (median: 93 vs. >140 months).

Conclusion: Aggressive BC subtypes occur among women with LFS. Surgical treatment, i.e. ME and CPM, may prolong time to a second BC diagnosis. Conclusion on long-term survival benefit is pending. Individual competing tumour risks and long-term outcomes need to be taken into consideration.
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http://dx.doi.org/10.1002/cam4.4300DOI Listing
September 2021

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets.

Cancer Discov 2021 Aug 9. Epub 2021 Aug 9.

Department of Pediatric Oncology and Hematology, University Hospital Magdeburg, Magdeburg, Germany.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0094DOI Listing
August 2021

Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors.

Pediatr Blood Cancer 2021 Dec 4;68(12):e29267. Epub 2021 Aug 4.

University Medical Center Augsburg, Paediatric and Adolescent Medicine, Swabian Children's Cancer Center, Augsburg, Germany.

Background: Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly.

Materials And Methods: A retrospective series of patients who received decitabine upon relapse or progression following therapy according to the EU-RHAB regimen is presented. Due to the retrospective nature of analyses, response was defined as measurable regression of at least one lesion on imaging. 850k methylation profiling was done whenever tumor tissue was available.

Results: A total of 22 patients with RT of any anatomical localization were included. Most patients (19/22) presented with metastases. All received low-dose decitabine with or preceding conventional chemotherapy. Patients received a median of two (1-6) courses of decitabine; 27.3% (6/22) demonstrated a radiological response. Molecular analyses revealed increased methylation levels in tumors from responders. No excessive toxicity was observed. Clinical benefits for responders included eligibility for early phase trials or local therapy. Responders showed prolonged time to progression and overall survival. Due to small sample size, statistical correction for survivorship bias demonstrated no significant effect on survival for responders.

Conclusions: Patients with RT demonstrate promising signs of antitumor activity after multiagent relapse therapy including decitabine. Analyses of methylation data suggest a specific effect on an epigenetic level. We propose to consider decitabine and other epigenetic drugs as candidates for further clinical investigations in RT.
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http://dx.doi.org/10.1002/pbc.29267DOI Listing
December 2021

Negative correlation of single-cell expression with tumorigenicity in rhabdomyosarcoma.

Life Sci Alliance 2021 09 29;4(9). Epub 2021 Jun 29.

Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany

Rhabdomyosarcomas (RMS) are phenotypically and functionally heterogeneous. Both primary human RMS cultures and low-passage mouse RMS cell lines, which express the fusion oncoprotein Pax3:Foxo1 and lack the tumor suppressor (), exhibit marked heterogeneity in () expression at the single cell level. In mouse RMS cells, expression is directed by the promoter and coupled to YFP/P3F mouse RMS cells included 87% G0/G1 cells and reorganized their actin cytoskeleton to produce a cellular phenotype characterized by more efficient adhesion and migration. This translated into higher tumor-propagating cell frequencies of YFP/P3F compared with YFP/P3F cells. Both YFP/P3F and YFP/P3F cells gave rise to mixed clones in vitro, consistent with fluctuations in expression over time. Exposure to the anti-tropomyosin compound TR100 disrupted the cytoskeleton and reversed enhanced migration and adhesion of YFP/P3F RMS cells. Heterogeneous expression of at the single cell level may provide a critical advantage during tumor progression.
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http://dx.doi.org/10.26508/lsa.202001002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321661PMC
September 2021

A Study of Regulatory Challenges of Pediatric Oncology Phase I/II Trial Submissions and Guidance on Protocol Development.

Clin Pharmacol Ther 2021 10 12;110(4):1025-1037. Epub 2021 Jul 12.

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.

The purpose of this study was to identify key deficiencies in pediatric oncology early phase clinical trial protocols in Germany and to provide guidance for efficient trial protocol development. A systematic review of the response letters of German competent authorities (CAs) and Ethics Committees to phase I/II pediatric oncology trial submissions in the period from 2014 to 2019 was performed. Documents were requested from all five Society for Paediatric Oncology and Haematology in Germany (GPOH) phase I/II trial networks plus all nine German Innovative Therapies for Children with Consortium Cancer (ITCC) centers. A blinded dataset containing aggregated data from 33 studies was analyzed for validation. All deficiencies were reviewed, listed, and weighted using a structured matrix according to frequency, category, significance, and feasibility. In total, documents of 17 trials from 6 different sites were collected. Two hundred fifty deficiencies identified by the CAs were identified and categorized into eight categories. "Toxicity and safety" was the most prominent category (27.6%), followed by "Manufacturing and Import" (18%). The majority of deficiencies were categorized as minor and potential measures as easy to address, but an important group of major and difficult to implement deficiencies was also identified. The blinded validation dataset confirmed these findings. The majority of the EC deficiencies could be resolved by changing the wording in the patient-facing documents. In conclusion, this study was able to detect a pattern of key deficiencies. Most of the shortcomings can be anticipated by minor changes in the protocol and increased awareness can prevent time-consuming revisions, withdrawals, or even rejections. A corresponding guideline describing key regulatory aspects is provided.
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http://dx.doi.org/10.1002/cpt.2319DOI Listing
October 2021

Utilization of Interdisciplinary Tumor Boards for Sarcoma Care in Germany: Results from the PROSa Study.

Oncol Res Treat 2021 22;44(6):301-312. Epub 2021 Apr 22.

Clinic and Polyclinic for Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.

Background: Data on institutional structures of sarcoma care in Germany are scarce. The utilization of an interdisciplinary tumor board (IDTB) is an essential part of modern cancer care. We investigated to which extent and when IDTB are used in sarcoma care. We hypothesized that IDTB before treatment initiation were used more often at certified cancer centers and at high-volume centers and that IDTB utilization increased over time.

Methods: From 2017 to 2020 we conducted a prospective cohort study, undertaking major efforts to include the whole spectrum of sarcoma treatment facilities. To analyze potential predictors of IDTB utilization, we calculated multivariable logistic regressions.

Results: Patients and survivors (n = 1,309) from 39 study centers (22 tertiary referral hospitals, 9 other hospitals, and 8 office-based practices) participated; 88.3% of the patients were discussed at some stage of their disease in an IDTB (56.1% before treatment, 78% after therapy, and 85.9% in metastatic disease). Hypotheses were confirmed regarding the utilization of IDTB in certified cancer centers (vs. all others: OR = 5.39; 95% CI 3.28-8.85) and the time of diagnosis (2018/2019 vs. until 2013: OR = 4.95; 95% CI 2.67-9.21).

Conclusion: Our study adds to the evidence regarding the institutional structures of sarcoma care in Germany. Utilization of a tumor board before therapy seems to be in an implementation process that is making progress but is far from complete. Certification is a possible tool to accelerate this development.
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http://dx.doi.org/10.1159/000516262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220922PMC
September 2021

Transitioning the Molecular Tumor Board from Proof of Concept to Clinical Routine: A German Single-Center Analysis.

Cancers (Basel) 2021 Mar 8;13(5). Epub 2021 Mar 8.

Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Molecular precision oncology faces two major challenges: first, to identify relevant and actionable molecular variants in a rapidly changing field and second, to provide access to a broad patient population. Here, we report a four-year experience of the Molecular Tumor Board (MTB) of the Comprehensive Cancer Center Freiburg (Germany) including workflows and process optimizations. This retrospective single-center study includes data on 488 patients enrolled in the MTB from February 2015 through December 2018. Recommendations include individual molecular diagnostics, molecular stratified therapies, assessment of treatment adherence and patient outcomes including overall survival. The majority of MTB patients presented with stage IV oncologic malignancies (90.6%) and underwent an average of 2.1 previous lines of therapy. Individual diagnostic recommendations were given to 487 patients (99.8%). A treatment recommendation was given in 264 of all cases (54.1%) which included a molecularly matched treatment in 212 patients (43.4%). The 264 treatment recommendations were implemented in 76 patients (28.8%). Stable disease was observed in 19 patients (25.0%), 17 had partial response (22.4%) and five showed a complete remission (6.6%). An objective response was achieved in 28.9% of cases with implemented recommendations and for 4.5% of the total population (22 of 488 patients). By optimizing the MTB workflow, case-discussions per session increased significantly while treatment adherence and outcome remained stable over time. Our data demonstrate the feasibility and effectiveness of molecular-guided personalized therapy for cancer patients in a clinical routine setting showing a low but robust and durable disease control rate over time.
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http://dx.doi.org/10.3390/cancers13051151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962829PMC
March 2021

Rationale for the use of tyrosine kinase inhibitors in the treatment of paediatric desmoid-type fibromatosis.

Br J Cancer 2021 May 15;124(10):1637-1646. Epub 2021 Mar 15.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.

In children with desmoid-type fibromatosis (DTF) in whom disease progression occurs after an initial watch-and-wait strategy, prolonged low-dose chemotherapy using vinblastine and methotrexate (VBL-MTX) is currently the standard of care. These conventional drugs have been prospectively evaluated but their efficacy and safety profiles are limited, and alternative therapeutic options are therefore essential. Based on the results of clinical trials, the use of tyrosine kinase inhibitors (TKIs) in the treatment of DTF is currently considered only in adult patients. TKIs such as imatinib show superior therapeutic efficacy to VBL-MTX and tolerable short-term side effects for the treatment of adult DFT, supporting the concept of the use of TKIs for the treatment of paediatric DFT. Moreover, new-generation TKIs, such as pazopanib and sorafenib, have shown improved therapeutic efficacy compared to imatinib in adult non-comparative studies. A tolerable safety profile of TKI therapy in children with disease entities other than DTF, such as leukaemia, has been reported. However, the efficacy and, in particular, the long-term safety of TKIs, including childhood-specific aspects such as growth and fertility, for the treatment of children with DTF should be investigated prospectively, as DFT therapy requires long-term drug exposure.
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http://dx.doi.org/10.1038/s41416-021-01320-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110972PMC
May 2021

Lack of Electron Acceptors Contributes to Redox Stress and Growth Arrest in Asparagine-Starved Sarcoma Cells.

Cancers (Basel) 2021 Jan 22;13(3). Epub 2021 Jan 22.

Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany.

Amino acids are integral components of cancer metabolism. The non-essential amino acid asparagine supports the growth and survival of various cancer cell types. Here, different mass spectrometry approaches were employed to identify lower aspartate levels, higher aspartate/glutamine ratios and lower tricarboxylic acid (TCA) cycle metabolite levels in asparagine-deprived sarcoma cells. Reduced nicotinamide adenine dinucleotide (NAD)/nicotinamide adenine dinucleotide hydride (NADH) ratios were consistent with redirection of TCA cycle flux and relative electron acceptor deficiency. Elevated lactate/pyruvate ratios may be due to compensatory NAD regeneration through increased pyruvate to lactate conversion by lactate dehydrogenase. Supplementation with exogenous pyruvate, which serves as an electron acceptor, restored aspartate levels, NAD/NADH ratios, lactate/pyruvate ratios and cell growth in asparagine-deprived cells. Chemicals disrupting NAD regeneration in the electron transport chain further enhanced the anti-proliferative and pro-apoptotic effects of asparagine depletion. We speculate that reductive stress may be a major contributor to the growth arrest observed in asparagine-starved cells.
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http://dx.doi.org/10.3390/cancers13030412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865502PMC
January 2021

Pathology of childhood rhabdomyosarcoma: A consensus opinion document from the Children's Oncology Group, European Paediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

Pediatr Blood Cancer 2021 03 11;68(3):e28798. Epub 2020 Dec 11.

Dipartimento per la Salute della Donna e del Bambino, University of Padova, Padova, Italy.

The diagnosis and classification of rhabdomyosarcoma (RMS) has undergone several shifts over the last 30 years. While the main diagnostic categories remained the same, changes in the histologic criteria necessary for diagnosis, as well as varied reliance on immunohistochemical and molecular data over time, have created confusion, particularly regarding how these shifts impacted risk stratification and enrollment onto clinical trials. The goal of this report is to review the evolution and current status of RMS diagnosis, focusing on diagnostic criteria in the Children's Oncology Group (COG), the European Paediatric Soft Tissue Sarcoma Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). In addition, we emphasize research tools used to classify RMS and address biological questions within current clinical trials run by each group. The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) initiative will maximize potential to optimize risk stratification by recognizing and accounting for differences in historical data and current practices.
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http://dx.doi.org/10.1002/pbc.28798DOI Listing
March 2021

[Diagnosis and therapy of tumors with NTRK gene fusion].

Pathologe 2021 Feb;42(1):103-115

Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Deutschland.

NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.
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http://dx.doi.org/10.1007/s00292-020-00864-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858552PMC
February 2021

In Reply: Comments About Patterns of Prior and Subsequent Neoplasms in Children and Adolescents With Soft Tissue Sarcomas.

J Pediatr Hematol Oncol 2021 04;43(3):116-117

Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, University of Freiburg Mathildenstrasse, Freiburg, Germany.

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http://dx.doi.org/10.1097/MPH.0000000000002001DOI Listing
April 2021

Impact of COVID-19 in paediatric early-phase cancer clinical trials in Europe: A report from the Innovative Therapies for Children with Cancer (ITCC) consortium.

Eur J Cancer 2020 12 9;141:82-91. Epub 2020 Oct 9.

Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Introduction: Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC).

Methods: A survey was sent to all ITCC-accredited early-phase clinical trial hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1st March and 30th April 2020.

Results: Thirty-one of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared with that in 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. In addition, 26% of sites had restrictions on performing trial assessments because of local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organisational and structural changes.

Conclusion: The study reveals a profound disruption of paediatric cancer early-phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises.
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http://dx.doi.org/10.1016/j.ejca.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546235PMC
December 2020

Case Report: Hepatic Adenoma in a Child With a Congenital Extrahepatic Portosystemic Shunt.

Front Pediatr 2020 25;8:501. Epub 2020 Aug 25.

Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg im Breisgau, Germany.

Congenital extrahepatic portosystemic shunts (CEPS), previously also described as Abernethy malformations, are rare malformations in which the extrahepatic portal system directly communicates with the vena cava inferior, thereby bypassing the liver. A hypoplastic portal vein (PV) exists in most cases. CEPS have been associated with the development of liver nodules, ranging from mostly focal nodular hyperplasia (FNH) to hepatic adenoma (HA) and even hepatocellular carcinoma (HCC). Tumor development in CEPS may be due to changes in perfusion pressures, oxygen supply or endocrine imbalances. It is important to rule out CEPS in children with liver tumors, because resection could impede future shunt occlusion procedures, and benign masses may regress after shunt occlusion. Here, we review the case of a 9-years-old male with CEPS and hepatic nuclear Factor 1-alpha (HNF-1-alpha) inactivated HA to raise awareness of this condition and review histopathological changes in the liver of CEPS.
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http://dx.doi.org/10.3389/fped.2020.00501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477041PMC
August 2020

Growth inhibition associated with disruption of the actin cytoskeleton by Latrunculin A in rhabdomyosarcoma cells.

PLoS One 2020 8;15(9):e0238572. Epub 2020 Sep 8.

Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

Functional genomic screening of KRAS-driven mouse sarcomas was previously employed to identify proliferation-relevant genes. Genes identified included Ubiquitin-conjugating enzyme E2 (Ube2c), Centromere Protein E (Cenpe), Hyaluronan Synthase 2 (Has2), and CAMP Responsive Element Binding Protein 3 Like 2 (Creb3l2). This study examines the expression and chemical inhibition of these candidate genes, identifying variable levels of protein expression and significant contributions to rhabdomyosarcoma (RMS) cell proliferation. Chemical treatment of human and murine RMS cell lines with bortezomib, UA62784, latrunculin A and sorafenib inhibited growth with approximate EC50 concentrations of 15-30nM for bortezomib, 25-80nM for UA62784 and 80-220nM for latrunculin A. The multi-kinase inhibitor sorafenib increased in vitro proliferation of 4 of 6 sarcoma cell lines tested. Latrunculin A was further associated with disruption of the actin cytoskeleton and reduced ERK1/2 phosphorylation. Together, this work advances opportunities for developing therapies to block progression of soft-tissue sarcomas and demonstrates that disruption of the actin cytoskeleton in sarcoma cells by latrunculin A is associated with a reduction in RMS cell growth. (167 words).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238572PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478754PMC
October 2020

Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group.

Fam Cancer 2021 Oct 5;20(4):327-336. Epub 2020 Sep 5.

De Duve Institute, University of Louvain, Brussels, Belgium.

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variants. Somatic PDGFRB variants were also detected in solitary and multifocal IM lesions. PDGFRB variants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRB germline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.
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http://dx.doi.org/10.1007/s10689-020-00204-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484085PMC
October 2021

Spotlight on the treatment of infantile fibrosarcoma in the era of neurotrophic tropomyosin receptor kinase inhibitors: International consensus and remaining controversies.

Eur J Cancer 2020 09 9;137:183-192. Epub 2020 Aug 9.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori di Milano, Milano, Italy.

Targeted neurotrophic tropomyosin receptor kinase (TRK) inhibitors offer a highly specific therapeutic option for patients with infantile fibrosarcoma (IFS) carrying the NTRK gene translocation. International recommendations are needed to define the role of TRK inhibitors (TRKI) for infants with IFS. We analysed retrospective data for all published patients with IFS in the European Paediatric Soft tissue sarcoma Study Group and Cooperative Weichteilsarkomstudiengruppe (CWS) experience and developed a consensus strategy with the Children's Oncology Group. Therapies consisted of tumour resection and/or perioperative chemotherapy for extensive tumours. Among the 172 European patients treated, 162 were alive at the end of the follow-up. Sixty-five patients (40% of all survivors) were treated with surgery alone and 64 patients (39%) with surgery combined with chemotherapy. Radiotherapy was delivered to 3% of survivors (five patients). In addition, 28 survivors (17%) exclusively received chemotherapy. Among the 129 patients treated with surgery, 91% had conservative surgery (118 cases). Overall, nine patients died of disease, one from toxicity (6%) and 20 patients (12%) survived with major functional deficits or had mutilating surgery. Overall, conventional conservative strategies before the era of targeted therapy, even in the case of extensive tumours, demonstrate efficacy in IFS, but are associated with acute and some chronic side effects. TRKI have demonstrated very rapid responses in the vast majority of children with IFS with limited acute toxicity. With the current state of our knowledge, both conventional chemotherapy and TRKI should be regarded as options for patients with localised disease at the physician's and parent's discretion. TRKI should be considered in patients with metastatic disease, and before mutilating surgery when conventional chemotherapy fails. Outside a clinical trial, additional data are needed to resolve the lack of consensus about front-line use of conventional chemotherapy versus TRKI in patients with localised disease.
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http://dx.doi.org/10.1016/j.ejca.2020.06.028DOI Listing
September 2020

Patterns of Prior and Subsequent Neoplasms in Children and Adolescents With Soft Tissue Sarcomas.

J Pediatr Hematol Oncol 2020 07;42(5):e265-e270

Department of Pediatric and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Medical Center Freiburg, University of Freiburg.

Background: The occurrence of prior, concurrent and subsequent neoplasms (SN) represents a serious problem in children and adolescents with soft tissue sarcomas. Pathogenic germline variants contribute to the diagnosis of multiple neoplasms in sarcoma survivors.

Materials And Methods: The records of 748 children and adolescents, diagnosed with soft tissue sarcomas and registered in trials/registries by the cooperative soft tissue sarcoma (Cooperative Weichteilsarkom Studie) group, were reviewed for the occurrence of SNs. Reference histology review was available for all cases; the presence of oncogenic fusions known at the time of diagnosis was confirmed for fusion-positive (F+) entities.

Results: Concurrent or subsequent SNs developed in 13 of 473 survivors of fusion-negative (F-) sarcomas, for an 8-year cumulative SN incidence of 5% in survivors of F- sarcomas. In contrast, only 1 of 278 survivors of F+ sarcoma developed an SN. Twenty of 748 patients with soft tissue sarcomas had a history of prior neoplasms. Six of 14 patients who developed SNs after their index sarcomas met Chompret criteria for Li-Fraumeni syndrome. Nine of 20 patients who had tumors before their index sarcoma diagnosis had neurofibromatosis type 1 or neurofibromatosis type 1 spectrum tumors.

Conclusion: Sarcoma phenotype/genotype and the sequence and nature of prior and subsequent neoplasms provide a window into underlying germline genetic susceptibilities in children and adolescents with soft tissue sarcomas.
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http://dx.doi.org/10.1097/MPH.0000000000001837DOI Listing
July 2020

Cancer surveillance and distress among adult pathogenic TP53 germline variant carriers in Germany: A multicenter feasibility and acceptance survey.

Cancer 2020 09 18;126(17):4032-4041. Epub 2020 Jun 18.

Department of Gynecology and Obstetrics, University Hospital Heidelberg, Heidelberg, Germany.

Background: Li-Fraumeni syndrome (LFS) is a high-risk cancer predisposition syndrome caused by pathogenic germline variants of TP53. Cancer surveillance has noted a significant survival advantage in individuals with LFS; however, little is known about the feasibility, acceptance, and psychosocial effects of such a program.

Methods: Pathogenic TP53 germline variant carriers completed a 7-part questionnaire evaluating sociodemographics, cancer history, surveillance participation, reasons for nonadherence, worries, and distress adapted from the Cancer Worry Scale. Counselees' common concerns and suggestions were assessed in MAXQDA Analytics Pro 12.

Results: Forty-nine participants (46 females and 3 males), aged 40.0 ± 12.6 years, formed the study population; 43 (88%) had a personal cancer history (including multiple cancers in 10 [20%]). Forty-three individuals participated (88%) in surveillance during the study or formerly. Willingness to undergo surveillance was influenced by satisfaction with genetic testing and counseling (P = .019 [Fisher-Yates test]) but not by sociodemographics, cancer history, or distress level. Almost one-third of the participants reported logistical difficulties in implementing surveillance because of the high frequency of medical visits, scheduling difficulties, and the travel distance to their surveillance providers. Self-reported distress and perceived emotional burden for family members and partners were moderate (median for self-reported distress, 3.3; median for perceived emotional burden, 3.0). For both, the interquartile range was moderate to very high (2.7-3.7 and 3.0-3.7, respectively).

Conclusions: Individuals with LFS require efficient counseling as well as an accessible, well-organized, interdisciplinary, standardized surveillance program to increase adherence and psychological coping.
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http://dx.doi.org/10.1002/cncr.33004DOI Listing
September 2020

Dermatofibrosarcoma protuberans in children and adolescents: Primary and Relapsed disease-Experience of the Cooperative Weichteilsarkomstudiengruppe (CWS).

J Surg Oncol 2020 Aug 19;122(2):263-272. Epub 2020 May 19.

Klinikum Stuttgart-Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare low-grade tumor. Little is known about best treatment of primary and relapsed disease (RD).

Methods: Treatment and outcome of 40 patients with DFSP prospectively registered within the CWS-96 and -2002P trials and the registry SoTiSaR (1996-2016) were analysed.

Results: Median age was 8 years (range, 0.64-17.77). Fluorescence in situ hybridization analysis to detect COL1A1-PDGFB fusion genes was positive in 86% (12/14) of evaluated patients. Primary resection was performed in all patients. Patients had IRS group I (n = 28), II (n = 9), and III (n = 2); not available (n = 1). To achieve complete remission (CR), a secondary resection was performed in 18 patients resulting in microscopically complete (R0, n = 34/40) and microscopically incomplete (R1, n = 5/40) resection. All patients achieved CR. The 5-year event-free survival (EFS) and overall survival was 86% (±12; CI, 95%) and 100% (±0; CI, 95%), respectively. R0 resection/IRS I was significantly favorable for the 5-year EFS. Local relapse occurred after a median time of 1.1 years (range, 0.04-5.1) in 15% (6/40) after CR. All patients with RD underwent resection and achieved CR. Three patients had fibrosarcomatous DFSP, two were alive after R0 resection.

Conclusion: Complete surgical resection is mandatory to prevent relapse of DFSP.
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http://dx.doi.org/10.1002/jso.25943DOI Listing
August 2020

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Cancer Discov 2020 07 1;10(7):942-963. Epub 2020 Apr 1.

Department of Neuropathology, University Hospital Hamburg-Eppendorf, and Research Institute Children's Cancer Center, Hamburg, Germany.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ( = 31), ( = 21), ( = 9), and ( = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of , or gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313225PMC
July 2020

Endothelial cell malignancies in infants, children and adolescents: Treatment results of three Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Pediatr Blood Cancer 2020 03 8;67(3):e28095. Epub 2019 Dec 8.

Department for Children and Adolescents, University of Frankfurt, Frankfurt am Main, Germany.

Background: Endothelial cell malignancies are extremely rare in childhood. New identification of genetic abnormalities (WWTR1:CAMTA1 translocation) helps to recognize potential therapeutic targets. Little is known about treatment and outcome of these patients.

Methods: Clinical course, treatment, and outcome in patients with endothelial cell malignancies treated within the Cooperative Weichteilsarkom Studiengruppe (CWS) trials CWS-91, -96, -2002P, and the Soft-Tissue Sarcoma Registry (SoTiSaR) were analyzed (1991-2019).

Results: Patients had angiosarcoma (AS) (n = 12), malignant epithelioid hemangioendothelioma (EHE) (n = 16), and kaposiform hemangioendothelioma (KHE) (n = 13). The median age was 5.39 years (range, 0.8-17.34); 33 patients had localized disease (LD), and 8 patients had metastatic disease. Therapy consisted of chemotherapy (CHT) (AS n = 8, EHE n = 9, KHE n = 5), interferon or new agent therapy (EHE n = 5, 2 KHE n = 2), microscopically or macroscopically complete resection (AS n = 3, EHE n = 6, KHE n = 3), and radiotherapy (AS n = 6, EHE n = 2, KHE n = 1). Two patients (KHE) had watch-and-wait strategy resulting in stable disease. Complete remission (CR) was achieved in AS (10/12; 83%), EHE (10/16; 63%), and KHE (5/13; 38%). The five-year EFS and OS for patients with AS was 64% (± 29 CI 95%) and 80% (± 25, CI 95%), with EHE 62% (± 24, CI 95%) and 78% (± 23, CI 95%), with KHE 33% (± 34, CI 95%) and 92% (± 15, CI 95%), respectively. Complete resection was a significant prognostic factor for AS, LD for EHE.

Conclusions: Endothelial cell malignancies in childhood have a fair outcome with multimodal treatment. New treatment options are needed for metastic disease.
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http://dx.doi.org/10.1002/pbc.28095DOI Listing
March 2020

Sarcoma of the Uterus. Guideline of the DGGG and OEGGG (S2k Level, AWMF Register Number 015/074, February 2019).

Geburtshilfe Frauenheilkd 2019 Oct 22;79(10):1043-1060. Epub 2019 Oct 22.

Frauenklinik, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg; Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany.

This is an official guideline published and coordinated by the German Society of Gynecology and Obstetrics (DGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Because of their rarity and heterogeneous histopathology, uterine sarcomas are challenging in terms of how they should be managed clinically, and treatment requires a multidisciplinary approach. To our knowledge, there are currently no binding evidence-based recommendations for the appropriate management of this heterogeneous group of tumors. This S2k guideline was first published in 2015. The update published here is the result of the consensus of a representative interdisciplinary group of experts who carried out a systematic search of the literature on uterine sarcomas in the context of the guidelines program of the DGGG, OEGGG and SGGG. Members of the participating professional societies achieved a formal consensus after a moderated structured consensus process. The consensus-based recommendations and statements include the epidemiology, classification, staging, symptoms, general diagnostic work-up and general pathology of uterine sarcomas as well as the genetic predisposition to develop uterine sarcomas. Also included are statements on the management of leiomyosarcomas, (low and high-grade) endometrial stromal sarcomas and undifferentiated uterine sarcomas and adenosarcomas. Finally, the guideline considers the follow-up and morcellation of uterine sarcomas and the information provided to patients.
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http://dx.doi.org/10.1055/a-0882-4116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805182PMC
October 2019

Insights into pediatric rhabdomyosarcoma research: Challenges and goals.

Pediatr Blood Cancer 2019 10 21;66(10):e27869. Epub 2019 Jun 21.

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.
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http://dx.doi.org/10.1002/pbc.27869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707829PMC
October 2019

Myxoid liposarcoma: it's a hippo's world.

EMBO Mol Med 2019 05;11(5)

Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.15252/emmm.201910470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505570PMC
May 2019

Rhabdomyosarcoma diagnosed in the first year of life: Localized, metastatic, and relapsed disease. Outcome data from five trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS).

Pediatr Blood Cancer 2019 06 14;66(6):e27652. Epub 2019 Feb 14.

Department for Children and Adolescents, University Hospital of Frankfurt, Frankfurt/M., Germany.

Background: Rhabdomyosarcoma (RMS) diagnosed during the first year of life is reported to have poor outcome. Little is known about treatment and outcome data of relapsed disease (RD).

Methods: Characteristics, treatment, and outcome of 155 patients ≤ 12 months registered within the Cooperative Weichteilsarkom Studiengruppe (CWS) between 1981 and 2016 were evaluated.

Results: Localized disease (LD) was diagnosed in 144 patients and metastatic disease (MD) in 11. The histological diagnosis was alveolar (RMA) (n = 38, 23/25 examined patients PAX7/3:FOXO1-positive), embryonal (RME) (n = 100), botryoid (n = 10), anaplastic (n = 1), and spindle-cell RMS (n = 6). Multimodal treatment including conventional (age-adjusted) chemotherapy (CHT) (n = 150), resection (n = 137), and radiotherapy (RT) (n = 37) was administered. Complete remission was achieved in 129 of 144 patients with LD. RD occurred in 51 infants at a median age of 1.7 years (range, 0.3-8.8). Sixty-three percent of patients with RMA suffered RD, in contrast to 28% of patients with RME. Relapse treatment consisted of conventional CHT (n = 48), resection (n = 28), and RT (n = 21). The pattern of relapse and best resection were significant prognostic factors for patients with RD (P = 0.000 and P = 0.002). Late effects occurred as secondary malignancies in 6%, long-term toxicity in 21%, and resection-related impairment in 33% of the 105 surviving patients. The 5-year event-free survival and overall survival for infants with initial LD were 51% and 69%, 14% and 14% for patients with initial MD and 39% and 41% for relapsed patients, respectively.

Conclusion: Multimodal treatment including microscopically complete resection is strongly recommended to achieve a good prognosis in LD and RD of infants with RMS.
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http://dx.doi.org/10.1002/pbc.27652DOI Listing
June 2019

Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma.

Sci Rep 2018 10 23;8(1):15674. Epub 2018 Oct 23.

University of Aberdeen, School of Medicine, Medical Sciences and Nutrition, Foresterhill, Aberdeen, AB25 2ZD, Scotland.

Persistent hyperactivity of the Hippo effector YAP in activated satellite cells is sufficient to cause embryonal rhabdomyosarcoma (ERMS) in mice. In humans, YAP is abundant and nuclear in the majority of ERMS cases, and high YAP expression is associated with poor survival. However, YAP1 is rarely mutated in human ERMS. Instead, the most common mutations in ERMS are oncogenic RAS mutations. First, to compare YAP1 S127A and KRAS G12V-driven rhabdomyosarcomas, we re-analysed gene expression microarray datasets from mouse rhabdomyosarcomas caused by these genes. This revealed that only 20% of the up or downregulated genes are identical, suggesting substantial differences in gene expression between YAP and KRAS-driven rhabdomyosarcomas. As oncogenic RAS has been linked to YAP in other types of cancer, we also tested whether KRAS G12V alone or in combination with loss of p53 and p16 activates YAP in myoblasts. We found that neither KRAS G12V alone nor KRAS G12V combined with loss of p53 and p16 activated Yap or Yap/Taz-Tead1-4 transcriptional activity in C2C12 myoblasts or U57810 cells. In conclusion, whilst oncogenic KRAS mutation might activate Yap in other cell types, we could find no evidence for this in myoblasts because the expression of KRAS G12V expression did not change Yap/Taz activity in myoblasts and there was a limited overlap in gene expression between KRAS G12V and YAP1 S127A-driven tumours.
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http://dx.doi.org/10.1038/s41598-018-33852-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199242PMC
October 2018

Personalized Clinical Decision Making Through Implementation of a Molecular Tumor Board: A German Single-Center Experience.

JCO Precis Oncol 2018 16;2. Epub 2018 Aug 16.

University of Freiburg, Freiburg; , , , , , , , , , and , German Cancer Consortium, partner site Freiburg, and German Cancer Research Center, Heidelberg; , Augsburg Medical Center, Augsburg; and , University of Lübeck, Lübeck, Germany.

Purpose: Dramatic advances in our understanding of the molecular pathophysiology of cancer, along with a rapidly expanding portfolio of molecular targeted drugs, have led to a paradigm shift toward personalized, biomarker-driven cancer treatment. Here, we report the 2-year experience of the Comprehensive Cancer Center Freiburg Molecular Tumor Board (MTB), one of the first interdisciplinary molecular tumor conferences established in Europe. The role of the MTB is to recommend personalized therapy for patients with cancer beyond standard-of-care treatment.

Methods: This retrospective case series includes 198 patients discussed from March 2015 through February 2017. The MTB guided individual molecular diagnostics, assessed evidence of actionability of molecular alterations, and provided therapy recommendations, including approved and off-label treatments as well as available matched clinical trials.

Results: The majority of patients had metastatic solid tumors (73.7%), mostly progressive (77.3%) after a mean of 2.0 lines of standard treatment. Diagnostic recommendations resulted in 867 molecular diagnostic tests for 172 patients (five per case), including exome analysis in 36 cases (18.2%). With a median turnaround time of 28 days, treatment recommendations were given to 104 patients (52.5%). These included single-agent targeted therapies (42.3%), checkpoint inhibitors (37.5%), and combination therapies (18.3%). Treatment recommendations were implemented in 33 of 104 patients (31.7%), of whom 19 (57.6%) showed stable disease or partial response, including 14 patients (7.1% of the entire population) receiving off-label treatments.

Conclusion: Personalized extended molecular-guided patient care is effective for a small but clinically meaningful proportion of patients in challenging clinical situations. Limited access to targeted drugs, lack of trials, and submission at late disease stage prevents broader applicability, whereas genome-wide analyses are not a strict requirement for predictive molecular testing.
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http://dx.doi.org/10.1200/PO.18.00105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446498PMC
August 2018

Author Correction: The landscape of genomic alterations across childhood cancers.

Nature 2018 07;559(7714):E10

German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

In this Article, author Benedikt Brors was erroneously associated with affiliation number '8' (Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, USA); the author's two other affiliations (affiliations '3' and '7', both at the German Cancer Research Center (DKFZ)) were correct. This has been corrected online.
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http://dx.doi.org/10.1038/s41586-018-0167-2DOI Listing
July 2018

The landscape of genomic alterations across childhood cancers.

Nature 2018 03 28;555(7696):321-327. Epub 2018 Feb 28.

German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
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http://dx.doi.org/10.1038/nature25480DOI Listing
March 2018
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