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1.
J Transl Med ; 21(1): 342, 2023 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-37221626

RESUMEN

The Swedish Childhood Tumor Biobank (BTB) is a nonprofit national infrastructure for collecting tissue samples and genomic data from pediatric patients diagnosed with central nervous system (CNS) and other solid tumors. The BTB is built on a multidisciplinary network established to provide the scientific community with standardized biospecimens and genomic data, thereby improving knowledge of the biology, treatment and outcome of childhood tumors. As of 2022, over 1100 fresh-frozen tumor samples are available for researchers. We present the workflow of the BTB from sample collection and processing to the generation of genomic data and services offered. To determine the research and clinical utility of the data, we performed bioinformatics analyses on next-generation sequencing (NGS) data obtained from a subset of 82 brain tumors and patient blood-derived DNA combined with methylation profiling to enhance the diagnostic accuracy and identified germline and somatic alterations with potential biological or clinical significance. The BTB procedures for collection, processing, sequencing, and bioinformatics deliver high-quality data. We observed that the findings could impact patient management by confirming or clarifying the diagnosis in 79 of the 82 tumors and detecting known or likely driver mutations in 68 of 79 patients. In addition to revealing known mutations in a broad spectrum of genes implicated in pediatric cancer, we discovered numerous alterations that may represent novel driver events and specific tumor entities. In summary, these examples reveal the power of NGS to identify a wide number of actionable gene alterations. Making the power of NGS available in healthcare is a challenging task requiring the integration of the work of clinical specialists and cancer biologists; this approach requires a dedicated infrastructure, as exemplified here by the BTB.


Asunto(s)
Bancos de Muestras Biológicas , Neoplasias Encefálicas , Humanos , Niño , Suecia , Sistema Nervioso Central , Genómica
2.
Blood ; 118(22): 5783-93, 2011 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-21931115

RESUMEN

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.


Asunto(s)
Linfohistiocitosis Hemofagocítica/genética , Proteínas de la Membrana/genética , Células Cultivadas , Preescolar , Croacia , Análisis Mutacional de ADN , Dinamarca , Femenino , Finlandia , Humanos , Lactante , Recién Nacido , Intrones/genética , Linfohistiocitosis Hemofagocítica/clasificación , Masculino , Mutación/fisiología , Inversión de Secuencia/fisiología , Suecia , Ucrania
3.
J Neurooncol ; 107(1): 37-49, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21979893

RESUMEN

Medulloblastoma (MB) is a WHO grade IV, invasive embryonal CNS tumor that mainly affects children. The aggressiveness and response to therapy can vary considerably between cases, and despite treatment, ~30% of patients die within 2 years from diagnosis. Furthermore, the majority of survivors suffer long-term side-effects due to severe management modalities. Several distinct morphological features have been associated with differences in biological behavior, but improved molecular-based criteria that better reflect the underlying tumor biology are in great demand. In this study, we profiled a series of 25 MB with a 32K BAC array covering 99% of the current assembly of the human genome for the identification of genetic copy number alterations possibly important in MB. Previously known aberrations as well as several novel focally amplified loci could be identified. As expected, the most frequently observed alteration was the combination of 17p loss and 17q gain, which was detected in both high- and standard-risk patients. We also defined minimal overlapping regions of aberrations, including 16 regions of gain and 18 regions of loss in various chromosomes. A few noteworthy narrow amplified loci were identified on autosomes 1 (38.89-41.97 and 84.89-90.76 Mb), 3 (27.64-28.20 and 35.80-43.50 Mb), and 8 (119.66-139.79 Mb), aberrations that were verified with an alternative platform (Illumina 610Q chips). Gene expression levels were also established for these samples using Affymetrix U133Plus2.0 arrays. Several interesting genes encompassed within the amplified regions and presenting with transcript upregulation were identified. These data contribute to the characterization of this malignant childhood brain tumor and confirm its genetic heterogeneity.


Asunto(s)
Neoplasias Cerebelosas/genética , Aberraciones Cromosómicas , Amplificación de Genes , Dosificación de Gen , Perfilación de la Expresión Génica , Genoma Humano , Meduloblastoma/genética , Adolescente , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple/genética
5.
Front Med (Lausanne) ; 7: 604182, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33415118

RESUMEN

The unprecedented surge of nephrology inpatients needing kidney replacement therapy placed hospital systems under extreme stress during the COVID-19 pandemic. In this article, we describe the formation of a cross campus "New-York Presbyterian COVID-19 Kidney Replacement Therapy Task Force" with intercampus physician, nursing, and supply chain representation. We describe several strategies including the development of novel dashboards to track supply/demand of resources, urgent start peritoneal dialysis, in-house preparation of kidney replacement fluid, the use of unconventional personnel resources to ensure the safe and continued provision of kidney replacement therapy in the face of the unanticipated surge. These approaches facilitated equitable sharing of resources across a complex healthcare-system and allowed for the rapid implementation of standardized protocols at each hospital.

6.
Acta Paediatr ; 98(10): 1620-7, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19594464

RESUMEN

AIM: Primary tumours in the central nervous system (CNS) are the second most common malignancy in childhood after leukaemia. Sweden has a high incidence and a high-survival rate in international comparative studies. This has raised the question about the type of tumours included in the Swedish Cancer registry. We therefore compared international data to the Swedish Childhood Cancer registry. METHODS: Central nervous system tumours registered in the Swedish Childhood Cancer Registry were reclassified according to ICCC-3. Incidence and survival analyses were performed in the study population. RESULTS: There were 1479 children (<15 years) in Sweden diagnosed with CNS tumours 1984-2005. The distribution of diagnoses was similar to that reported in other studies. The annual incidence was 4.2/100,000 children. The survival rates have not improved significantly between the two time periods before/after 1995 (70% vs. 74%; p = 0.10). CONCLUSIONS: The mean annual incidence of children with CNS tumours was 4.2/100,000 and has not increased during the study period. Survival rate for brain tumours at 10 years follow-up was 72%.


Asunto(s)
Neoplasias del Sistema Nervioso Central/epidemiología , Mortalidad del Niño/tendencias , Glioma/epidemiología , Distribución por Edad , Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/terapia , Niño , Preescolar , Femenino , Glioma/mortalidad , Glioma/terapia , Humanos , Incidencia , Lactante , Masculino , Pronóstico , Sistema de Registros , Análisis de Regresión , Distribución por Sexo , Tasa de Supervivencia , Suecia/epidemiología
7.
Cancer Res ; 62(16): 4545-8, 2002 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-12183402

RESUMEN

Epigenetic lesions are common in neoplasia and range from hypermethylation of subsets of CpG islands to loss of imprinting. By exploiting an episomal model system and the strong de novo methylation capacity of a human cancer cell line, we show that an H19 minigene rapidly becomes methylated and silenced, mimicking the inactivation of the maternal H19 allele in a range of cancers. Although the H19 imprinting control region (ICR) initially displayed methylation protection, it eventually succumbed to the pressure mounted by the de novo methylation machinery of the JEG-3 cells. Importantly, we were able to visualize the kinetics of the loss of the H19 ICR chromatin insulator function in association with chromatin compaction. Our results document that a strong de novo methylation machinery leads to loss of methylation privilege states of H19 ICR to functionally manifest loss of insulator function in a matter of only a few days in human cancer cells.


Asunto(s)
Metilación de ADN , Impresión Genómica , Región de Control de Posición/genética , Neoplasias/genética , ARN no Traducido/genética , Animales , Coriocarcinoma/genética , Coriocarcinoma/metabolismo , Cromatina/genética , Cromatina/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Ratones , Neoplasias/metabolismo , ARN Largo no Codificante , ARN no Traducido/biosíntesis , Células Tumorales Cultivadas
8.
Adv Cancer Res ; 88: 145-68, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12665055

RESUMEN

Although the leading dogma for the origin of the diversity in cancer cell subpopulations is based on a stepwise selection and accumulation of genetic changes that allow uncontrollable malignant growth, there is an emerging understanding that the variability of heritable phenotypes in cancer and cancer-prone cells may also involve epigenetic mechanisms. We discuss here experimental data that allow us to postulate that the genome is organized into epigenetic territories with lineage-specific differences in the stringencies of the active and inactive states. Low-stringency epigenetic states are predicted to be closer to mosaicism, or chaos, than high-stringency states. In pathological situations, the result is an epigenetic variability upon which selection mechanisms can act during tumor progression. This view may have significant implications on clinical assessment and prognosis, and also suggests that major factors involved in the resetting and/or maintenance of epigenetic states may serve as new attractive targets for therapeutic interventions.


Asunto(s)
Variación Genética , Neoplasias/genética , Animales , Islas de CpG , Humanos , Mosaicismo , Dinámicas no Lineales
10.
PLoS One ; 9(9): e108861, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25268364

RESUMEN

Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.


Asunto(s)
Neoplasias Encefálicas/virología , Citomegalovirus/metabolismo , Fosfoproteínas/análisis , Proteínas de la Matriz Viral/análisis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/patología , Estudios de Cohortes , Citomegalovirus/aislamiento & purificación , Femenino , Glioblastoma/patología , Glioblastoma/virología , Humanos , Inmunohistoquímica , Linfoma/patología , Linfoma/virología , Masculino , Meduloblastoma/patología , Meduloblastoma/virología , Meningioma/patología , Meningioma/virología , Persona de Mediana Edad , Clasificación del Tumor , Adulto Joven
11.
Cancer Cell ; 26(5): 722-37, 2014 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-25517750

RESUMEN

Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors.


Asunto(s)
Biomarcadores de Tumor/fisiología , Proliferación Celular , Neuroblastoma/metabolismo , ARN Largo no Codificante/fisiología , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Humanos , Ratones , Trasplante de Neoplasias , Células-Madre Neurales/fisiología , Neuroblastoma/genética , Neuroblastoma/patología , Neurogénesis , Polimorfismo de Nucleótido Simple , Proteínas Represoras/metabolismo , Riesgo , Transcriptoma
12.
Neuro Oncol ; 11(6): 803-18, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19304958

RESUMEN

Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.


Asunto(s)
Neoplasias Encefálicas/genética , Aberraciones Cromosómicas , Cromosomas Artificiales Bacterianos , Perfilación de la Expresión Génica , Genes Relacionados con las Neoplasias , Glioblastoma/genética , Neoplasias Encefálicas/patología , Hibridación Genómica Comparativa , Femenino , Dosificación de Gen , Genoma Humano , Glioblastoma/patología , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Oncogenes , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
13.
Int J Cancer ; 119(3): 571-8, 2006 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16496407

RESUMEN

Wilms' tumor (WT) is one of the most common solid tumors of childhood. The genetics of this disorder is complex and few studies have suggested allelic loss of chromosome 22 as a frequent aberration. To assess tumor- and possible germline-specific regions affected with gene copy number variations on this chromosome, we applied a high-resolution genomic clone-based chromosome 22 array to a series of 28 WT samples and the paired blood-derived DNA of the patients. The group of tumors was enriched for cases with metastases, relapse or fatal outcome, criteria that were expected to yield a higher number of alterations on chromosome 22. Overall, the array-based form of comparative genomic hybridization (array-CGH) analysis revealed genomic changes in 53% (15 out of 28) of cases. We identified hemizygous deletion of the whole arm of 22q in 3 tumors (11%). Furthermore, a complex amplifier genotype was detected in 8 samples, presenting regions of gain along the chromosome, which defined 7 distinct minimal overlapping segments. The distribution of aberrations in 4 additional cases displaying regional genomic imbalances delimited 2 tumor suppressor/oncogene candidate loci, 1 in the proximal and the other in the terminal part of 22q. Analysis of these regions revealed the presence of several candidate genes that may play a role in the development of WT. These findings demonstrate the power of array-CGH in the determination of DNA copy number alterations and further strength the notion that WT-associated genes exist on this chromosome.


Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 22/genética , Neoplasias Renales/genética , Hibridación de Ácido Nucleico/métodos , Tumor de Wilms/genética , Niño , Preescolar , Deleción Cromosómica , Mapeo Cromosómico , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Femenino , Genoma Humano , Genotipo , Humanos , Lactante , Masculino , Monosomía
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