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Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.
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Trastorno del Espectro Autista , Trastorno Autístico , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Masculino , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/complicaciones , Proteína Fosfatasa 1/genética , Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Glucosa , Glucógeno , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/complicacionesRESUMEN
Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS-spectrum (LSS) cancers, including high-grade gliomas and colorectal cancer, causality has been supported by typical MMR-related tumor characteristics, but for non-LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non-LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non-LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR-deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non-LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS.
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Neoplasias Encefálicas , Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Síndromes Neoplásicos Hereditarios , Niño , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Neoplasias Colorrectales/patología , Neoplasias Encefálicas/genética , Mutación de Línea Germinal , Reparación de la Incompatibilidad de ADN/genética , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutL/genéticaRESUMEN
Hao-Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype-phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire-based study was performed to characterize the phenotype of Hao-Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao-Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome-specific severity score. This score neither indicates a sex- nor age-specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.
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Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Anomalías Craneofaciales , Sordera , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Peptidasa Específica de Ubiquitina 7/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/complicaciones , Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
BACKGROUND: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. METHODS: To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. RESULTS: Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. CONCLUSION: Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.
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A founder variant is a genetic alteration, that is inherited from a common ancestor together with a surrounding chromosomal segment, and is observed at a high frequency in a defined population. This founder effect occurs as a consequence of long-standing inbreeding of isolated populations. For high-risk cancer predisposition genes, such as BRCA1/2, the identification of founder variants in a certain population could help designing customized cost-effective cancer screening panels. This advantage has been best utilized in designing a customized breast cancer BRCA screening panel for the Ashkenazi Jews (AJ) population, composed of the three BRCA founder variants which account for approximately 90% of identified BRCA alterations. Indeed, the high prevalence of pathogenic BRCA1/2 variants among AJ (~ 2%) has additionally contributed to make population-based screening cost-effective in comparison to family-history-based screening. In Jordan there are multiple demographic characteristics supporting the proposal of a founder effect. A high consanguinity rate of ~ 57% in the nineties of the last century and ~ 30% more recently is a prominent factor, in addition to inbreeding which is often practiced by different sub-populations of the country.This review explains the concept of founder effect, then applies it to analyze published Jordanian BRCA variants, and concludes that nine pathogenic (P) and likely pathogenic (LP) BRCA2 variants together with one pathogenic BRCA1 variant are potential founder variants. Together they make up 43% and 55% of all identified BRCA1/2 alterations in the two largest studied cohorts of young patients and high-risk patients respectively. These variants were identified based on being recurrent and either specific to ethnic groups or being novel. In addition, the report highlights the required testing methodologies to validate these findings, and proposes a health economic evaluation model to test cost-effectiveness of a population-based customized BRCA screening panel for the Jordanian population. The aim of this report is to highlight the potential utilization of founder variants in establishing customized cancer predisposition services, in order to encourage more population-based genomic studies in Jordan and similar populations.
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Pathogenic variants in the BRCA1 and BRCA2 genes are well known causes of hereditary breast and ovarian cancer. Other genes involved in the homologous recombination pathway can also be associated with increased probability of cancer development, for example, breast and ovarian cancer, prostate and pancreatic cancer, colorectal cancer, and even childhood tumors like medulloblastoma. Traditionally, patients and families likely to harbor a genetic predisposition have been identified using personal and family history. Several checklists and risk prediction tools have proven to be useful in the clinic. Through the widespread application of next generation sequencing of tumor tissue, a growing number of individuals with genetic cancer predisposition is now identified molecularly, even in the absence of a suggestive family history. Any constitutional variant identified during molecular genetic testing has to be assessed for its relevance, both functionally and in the context of patient phenotype. Variant curation is time consuming, but has been increasingly standardized by introduction of several guidelines to allow reliable and reproducible classification of constitutional variants. Variant classification by expert panels using data mining tools, evidence-based decision trees and gene specific criteria represents the gold standard. Participation of geneticists in molecular tumor boards facilitates the curation of potential constitutional variants, germline validation and thus directing the patient to appropriate counselling and care pathways. Due to the high relevance of germline variants for treatment and surveillance of the index patient and predictive testing and surveillance of relatives, only pathogenic or likely pathogenic variants must be used for clinical decision-making.
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Pruebas Genéticas/métodos , Mutación de Línea Germinal , Neoplasias/genética , Reparación del ADN por Recombinación , Humanos , Neoplasias/diagnósticoRESUMEN
INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is a well-known complication following prolonged immunosuppression. Contrary to other lymphomas, there is no standardized imaging approach to assess PTLD either at staging or for response to therapy. Positron emission tomography/computed tomography (PET/CT) is an imaging modality that has proven to be useful in lymphoma. However, there is still limited data concerning its use in pediatric PTLD. Our study evaluates the use of PET/CT in pediatric PTLD at our institution. METHODS: To assess the role of PET/CT in pediatric PTLD, we reviewed the pediatric patients with PTLD who had undergone PET/CT at our institution between 2000 and 2016. RESULTS: Nine patients were identified. Six had PET/CT at diagnosis. All lesions seen on CT were identified with PET/CT. Fourteen PET/CTs were done during treatment. Eight PET/CTs were negative, including three where CT showed areas of uncertain significance. In these cases, PET/CT helped us to stop treatment and the patients remain in remission after a long follow-up (mean 74.3 months; range 12.4-180.9 months). PET/CT revealed additional disease in two cases, therefore treatment was intensified. Six biopsies and close follow-up was done to confirm PET/CT results. In one case, PET/CT did not identify central nervous system involvement demonstrated on magnetic resonance imaging. CONCLUSION: PET/CT may have an important role in the staging and follow-up of pediatric PTLD. In our cohort, PET/CT was helpful in staging and assessing treatment response and in clarifying equivocal findings on other imaging modalities.
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Trastornos Linfoproliferativos/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Complicaciones Posoperatorias/diagnóstico por imagen , Trasplante/efectos adversos , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Trastornos Linfoproliferativos/etiología , Masculino , Estadificación de Neoplasias , Complicaciones Posoperatorias/etiología , Estudios RetrospectivosRESUMEN
BACKGROUND: Precision oncology requires diagnostic accuracy and robust detection of actionable alterations. The Pediatric Targeted Therapy (PTT) 2.0 program aims at improving diagnostic accuracy by addition of molecular analyses to the existing histological diagnosis and detection of actionable alterations for relapsed paediatric oncology patients, in cases with limited availability of tumour material. METHODS: Paediatric patients diagnosed with relapse or progression of a central nervous system tumour (n = 178), a sarcoma (n = 41) or another solid tumour (n = 44) were included. DNA methylation array, targeted gene panel sequencing on tumour and blood (130 genes), RNA sequencing in selected cases and a pathway-specific immunohistochemistry (IHC) panel were performed using limited formalin-fixed paraffin embedded tissue from any disease episode available. The clinical impact of reported findings was assessed by a serial questionnaire-based follow-up. RESULTS: Integrated molecular diagnostics resulted in refined or changed diagnosis in 117/263 (44%) tumours. Actionable targets were detected in 155/263 (59%) cases. Constitutional DNA variants with clinical relevance were identified in 16/240 (7%) of patients, half of which were previously unknown. Clinical follow-up showed that 26/263 (10%) of patients received mechanism-of-action based treatment matched to the molecular findings. CONCLUSION: Next-generation diagnostics adds robust and relevant information on diagnosis, actionable alterations and cancer predisposition syndromes even when tissue from the current disease episode is limited.
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Patología Molecular , Sarcoma , Niño , Humanos , Medicina de Precisión/métodos , Recurrencia Local de Neoplasia/genética , ADN , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Terapia Molecular Dirigida/métodos , MutaciónRESUMEN
Analysis of selected cancer genes has become an important tool in precision oncology but cannot fully capture the molecular features and, most importantly, vulnerabilities of individual tumors. Observational and interventional studies have shown that decision-making based on comprehensive molecular characterization adds significant clinical value. However, the complexity and heterogeneity of the resulting data are major challenges for disciplines involved in interpretation and recommendations for individualized care, and limited information exists on how to approach multilayered tumor profiles in clinical routine. We report our experience with the practical use of data from whole-genome or exome and RNA sequencing and DNA methylation profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program of the National Center for Tumor Diseases (NCT) Heidelberg and Dresden and the German Cancer Research Center (DKFZ). We cover all relevant steps of an end-to-end precision oncology workflow, from sample collection, molecular analysis, and variant prioritization to assigning treatment recommendations and discussion in the molecular tumor board. To provide insight into our approach to multidimensional tumor profiles and guidance on interpreting their biological impact and diagnostic and therapeutic implications, we present case studies from the NCT/DKFZ molecular tumor board that illustrate our daily practice. This manual is intended to be useful for physicians, biologists, and bioinformaticians involved in the clinical interpretation of genome-wide molecular information.
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BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.
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Neoplasias Cerebelosas , Síndrome de Li-Fraumeni , Meduloblastoma , Niño , Humanos , Síndrome de Li-Fraumeni/complicaciones , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/terapia , Meduloblastoma/terapia , Meduloblastoma/tratamiento farmacológico , Estudios Retrospectivos , Estudios Prospectivos , Neoplasias Cerebelosas/terapia , Neoplasias Cerebelosas/tratamiento farmacológico , Mutación de Línea Germinal , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology.
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Neoplasias Encefálicas , Glioma , Adolescente , Humanos , Niño , Multiómica , Glioma/diagnóstico , Glioma/genética , Neuropatología , Metilación de ADN/genética , Mutación , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genéticaRESUMEN
A genetic predisposition to tumor development can be identified in up to 10% of pediatric patients with central nervous system (CNS) tumors. For some entities, the rate of an underlying predisposition is even considerably higher. In recent years, population-based approaches have helped to further delineate the role of cancer predisposition in pediatric oncology. Investigations for cancer predisposition syndrome (CPS) can be guided by clinical signs and family history leading to directed testing of specific genes. The increasingly adopted molecular analysis of tumor and often parallel blood samples with multi-gene panel, whole-exome, or whole-genome sequencing identifies additional patients with or without clinical signs. Diagnosis of a genetic predisposition may put an additional burden on affected families. However, information on a given cancer predisposition may be critical for the patient as potentially influences treatment decisions and may offer the patient and healthy carriers the chance to take part in intensified surveillance programs aiming at early tumor detection. In this review, we discuss some of the practical and ethical challenges resulting from the widespread use of new diagnostic techniques and the most important CPS that may manifest with brain tumors in childhood.
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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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Miofibromatosis , Niño , Preescolar , Pruebas Genéticas , Humanos , Mesilato de Imatinib , Miofibromatosis/diagnóstico , Miofibromatosis/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genéticaRESUMEN
PURPOSE: CATCH (Comprehensive Assessment of clinical feaTures and biomarkers to identify patients with advanced or metastatic breast Cancer for marker driven trials in Humans) is a prospective precision oncology program that uses genomics and transcriptomics to guide therapeutic decisions in the clinical management of metastatic breast cancer. Herein, we report our single-center experience and results on the basis of the first 200 enrolled patients of an ongoing trial. METHODS: From June 2017 to March 2019, 200 patients who had either primary metastatic or progressive disease, with any number of previous treatment lines and at least one metastatic site accessible to biopsy, were enrolled. DNA and RNA from tumor tissue and corresponding blood-derived nontumor DNA were profiled using whole-genome and transcriptome sequencing. Identified actionable alterations were brought into clinical context in a multidisciplinary molecular tumor board (MTB) with the aim of prioritizing personalized treatment recommendations. RESULTS: Among the first 200 enrolled patients, 128 (64%) were discussed in the MTB, of which 64 (50%) were subsequently treated according to MTB recommendation. Of 53 evaluable patients, 21 (40%) achieved either stable disease (n = 13, 25%) or partial response (n = 8, 15%). Furthermore, 16 (30%) of those patients showed improvement in progression-free survival of at least 30% while on MTB-recommended treatment compared with the progression-free survival of the previous treatment line. CONCLUSION: The initial phase of this study demonstrates that precision oncology on the basis of whole-genome and RNA sequencing is feasible when applied in the clinical management of patients with metastatic breast cancer and provides clinical benefit to a substantial proportion of patients.
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Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Medicina de Precisión , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Femenino , Genoma , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Prospectivos , TranscriptomaRESUMEN
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; P = 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.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659.
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Neoplasias , Niño , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Medicina de Precisión , Supervivencia sin Progresión , Estudios Prospectivos , Sistema de RegistrosRESUMEN
Chromothripsis is a form of genome instability by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosomes. Widely assumed to be an early event in tumor development, this phenomenon plays a prominent role in tumor onset. In this study, an analysis of chromothripsis in 252 human breast cancers from two patient cohorts (149 metastatic breast cancers, 63 untreated primary tumors, 29 local relapses, and 11 longitudinal pairs) using whole-genome and whole-exome sequencing reveals that chromothripsis affects a substantial proportion of human breast cancers, with a prevalence over 60% in a cohort of metastatic cases and 25% in a cohort comprising predominantly luminal breast cancers. In the vast majority of cases, multiple chromosomes per tumor were affected, with most chromothriptic events on chromosomes 11 and 17 including, among other significantly altered drivers, CCND1, ERBB2, CDK12, and BRCA1. Importantly, chromothripsis generated recurrent fusions that drove tumor development. Chromothripsis-related rearrangements were linked with univocal mutational signatures, with clusters of point mutations due to kataegis in close proximity to the genomic breakpoints and with the activation of specific signaling pathways. Analyzing the temporal order of events in tumors with and without chromothripsis as well as longitudinal analysis of chromothriptic patterns in tumor pairs offered important insights into the role of chromothriptic chromosomes in tumor evolution. SIGNIFICANCE: These findings identify chromothripsis as a major driving event in human breast cancer.
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Neoplasias de la Mama/genética , Cromotripsis , Reordenamiento Génico , Recurrencia Local de Neoplasia/genética , Algoritmos , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 17 , Ciclina D1/genética , Quinasas Ciclina-Dependientes/genética , Reparación del ADN , Femenino , Fusión Génica , Genes BRCA1 , Genes BRCA2 , Genes erbB-2 , Genes p53 , Humanos , Mutación INDEL , Transducción de Señal , Secuenciación del Exoma , Secuenciación Completa del GenomaRESUMEN
INTRODUCTION: For patients with primary refractory and relapsed acute leukaemias allogeneic stem cell transplantation is the only hope for cure, but morphological remission is not always achieved after standard salvage regimens. Here we review the experience with high-dose etoposide and cyclophosphamide (HD-Et/Cy) in relapsed/refractory acute leukaemias at the Royal Marsden Hospital. PATIENTS AND METHODS: Twenty-three patients (15 adults, 8 children) with refractory/relapsed acute myeloblastic (n = 18; 78%), lymphoblastic (n = 4; 17%) or biphenotypic (n = 1; 4%) leukaemia who had failed to respond to at least one previous line of chemotherapy received HD-Et/Cy at our institution between 2006 and 2015. RESULTS: Overall response rate was 21.7% (95%CI 4.0-40.0). Median overall survival was 14.8 months (95%CI 9.1-49.1). Eight (35%) patients (7 AML, 1 biphenotypic leukaemia) proceeded to allogeneic transplant after one cycle of HD-Et/Cy: four of them (50%; 3 adults, 1 child) in complete remission and another four children (50%) with aplastic bone marrow with scattered blasts. Among the transplant recipients, three with AML (38%), ie. one adult (responder) and two children with aplastic bone marrow with scattered blasts, became long-term survivors 9.8, 4.4 and 2.5 years post-HD-Et/Cy, respectively. Toxicity profile was comparable to similar regimens with no treatment-related deaths. The most common grade 3-4 toxicity was febrile neutropenia (96%). CONCLUSIONS: HD-Et/Cy can salvage patients with refractory/relapsed AML who remain candidates for allogeneic stem cell transplantation after failure of standard salvage regimens and do not have access to clinical trials.