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1.
Cell ; 148(1-2): 59-71, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22265402

RESUMO

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.


Assuntos
Neoplasias Encefálicas/genética , Rearranjo Gênico , Meduloblastoma/genética , Proteína Supressora de Tumor p53/genética , Animais , Criança , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Modelos Animais de Doenças , Humanos , Leucemia Mieloide Aguda/genética , Síndrome de Li-Fraumeni/fisiopatologia , Camundongos , Pessoa de Meia-Idade
2.
J Immunol ; 211(2): 229-240, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37294309

RESUMO

Immunotherapy development for solid tumors remains challenging, partially due to a lack of reproducible, cost-effective in vitro three-dimensional (3D) models to mimic the heterogeneous and complex tumor microenvironment. Here, we investigate the cellular anti-tumor reactivity of αß T cells engineered to express a defined γδ TCR (TEG A3). For that purpose, we developed a 3D cytotoxicity assay targeting cell line-derived spheroids or patient-derived tumor organoids formed in serum-free media. Tumor cell lysis by TEG A3 was monitored using the Incucyte S3 live-cell imaging system with the apoptosis marker caspase 3/7 green and endpoint readouts of IFN-γ secretion in the supernatant. The 3D cytotoxicity assay model system was able to adequately demonstrate TEG A3 reactivity toward targets expressing an isoform of CD277 (CD277J). To obtain a more complex heterogeneous tumor microenvironment, patient-derived organoids were mixed with unmatched patient-derived fibroblasts or matched cancer-associated fibroblasts. In all assays, we demonstrated the tumor target specificity of TEG A3, lysing tumor cells within 48 h. Our study demonstrates the utility of complex 3D cytotoxicity assay model systems incorporating the tumor microenvironment in the functional evaluation of T cell-based adoptive immunotherapy, providing a useful platform for early-stage preclinical development of immunotherapies.


Assuntos
Neoplasias , Humanos , Neoplasias/terapia , Linfócitos T , Imunoterapia Adotiva/métodos , Imunoterapia , Terapia Baseada em Transplante de Células e Tecidos , Microambiente Tumoral
3.
Nature ; 555(7696): 321-327, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29489754

RESUMO

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.


Assuntos
Genoma Humano/genética , Genômica , Mutação/genética , Neoplasias/classificação , Neoplasias/genética , Adolescente , Adulto , Criança , Cromotripsia , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Diploide , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Humanos , Terapia de Alvo Molecular , Taxa de Mutação , Neoplasias/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Adulto Jovem
5.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34479993

RESUMO

Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution.


Assuntos
Reparo do DNA/genética , Guanosina/análogos & derivados , Neuroblastoma/genética , Adenina/metabolismo , Criança , Citosina/metabolismo , Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Feminino , Guanina/metabolismo , Guanosina/genética , Guanosina/metabolismo , Humanos , Masculino , Mutagênese , Recidiva Local de Neoplasia/genética , Neuroblastoma/metabolismo , Estresse Oxidativo , Polimorfismo de Nucleotídeo Único/genética
6.
BMC Cancer ; 23(1): 310, 2023 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-37020198

RESUMO

BACKGROUND: Pediatric cancer is the leading cause of disease-related death in children and the need for better therapeutic options remains urgent. Due to the limited number of patients, target and drug development for pediatrics is often supplemented by data from studies focused on adult cancers. Recent evidence shows that pediatric cancers possess different vulnerabilities that should be explored independently from adult cancers. METHODS: Using the publicly available Genomics of Drug Sensitivity in Cancer database, we explore therapeutic targets and biomarkers specific to the pediatric solid malignancies Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. Results are validated using cell viability assays and high-throughput drug screens are used to identify synergistic combinations. RESULTS: Using published drug screening data, PARP is identified as a drug target of interest across multiple different pediatric malignancies. We validate these findings, and we show that efficacy can be improved when combined with conventional chemotherapeutics, namely topoisomerase inhibitors. Additionally, using gene set enrichment analysis, we identify ribosome biogenesis as a potential biomarker for PARP inhibition in pediatric cancer cell lines. CONCLUSION: Collectively, our results provide evidence to support the further development of PARP inhibition and the combination with TOP1 inhibition as a therapeutic approach in solid pediatric malignancies. Additionally, we propose ribosome biogenesis as a component to PARP inhibitor sensitivity that should be further investigated to help maximize the potential utility of PARP inhibition and combinations across pediatric solid malignancies.


Assuntos
Antineoplásicos , Neoplasias Cerebelares , Neuroblastoma , Sarcoma de Ewing , Humanos , Criança , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Antineoplásicos/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Neuroblastoma/patologia , Neoplasias Cerebelares/tratamento farmacológico , Linhagem Celular Tumoral
7.
BMC Cancer ; 23(1): 618, 2023 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-37400763

RESUMO

BACKGROUND: Gene fusions are important cancer drivers in pediatric cancer and their accurate detection is essential for diagnosis and treatment. Clinical decision-making requires high confidence and precision of detection. Recent developments show RNA sequencing (RNA-seq) is promising for genome-wide detection of fusion products but hindered by many false positives that require extensive manual curation and impede discovery of pathogenic fusions. METHODS: We developed Fusion-sq to overcome existing disadvantages of detecting gene fusions. Fusion-sq integrates and "fuses" evidence from RNA-seq and whole genome sequencing (WGS) using intron-exon gene structure to identify tumor-specific protein coding gene fusions. Fusion-sq was then applied to the data generated from a pediatric pan-cancer cohort of 128 patients by WGS and RNA sequencing. RESULTS: In a pediatric pan-cancer cohort of 128 patients, we identified 155 high confidence tumor-specific gene fusions and their underlying structural variants (SVs). This includes all clinically relevant fusions known to be present in this cohort (30 patients). Fusion-sq distinguishes healthy-occurring from tumor-specific fusions and resolves fusions in amplified regions and copy number unstable genomes. A high gene fusion burden is associated with copy number instability. We identified 27 potentially pathogenic fusions involving oncogenes or tumor-suppressor genes characterized by underlying SVs, in some cases leading to expression changes indicative of activating or disruptive effects. CONCLUSIONS: Our results indicate how clinically relevant and potentially pathogenic gene fusions can be identified and their functional effects investigated by combining WGS and RNA-seq. Integrating RNA fusion predictions with underlying SVs advances fusion detection beyond extensive manual filtering. Taken together, we developed a method for identifying candidate gene fusions that is suitable for precision oncology applications. Our method provides multi-omics evidence for assessing the pathogenicity of tumor-specific gene fusions for future clinical decision making.


Assuntos
Neoplasias , Criança , Humanos , Neoplasias/genética , RNA-Seq , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Medicina de Precisão , Análise de Sequência de RNA/métodos , Fusão Gênica , Sequenciamento Completo do Genoma
8.
Cancer Sci ; 113(6): 2167-2178, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35384159

RESUMO

Neuroblastoma is the most common extracranial solid tumor in children. The chromatin remodeler ATRX is frequently mutated in high-risk patients with a poor prognosis. Although many studies have reported ATRX aberrations and the associated clinical characteristics in neuroblastoma, a comprehensive overview is currently lacking. In this study, we extensively characterize the mutational spectrum of ATRX aberrations in neuroblastoma tumors reported in previous studies and present an overview of patient and tumor characteristics. We collected the data of a total of 127 neuroblastoma patients and three cell lines with ATRX aberrations originating from 20 papers. We subdivide the ATRX aberrations into nonsense, missense, and multiexon deletions (MEDs) and show that 68% of them are MEDs. Of these MEDs, 75% are predicted to be in-frame. Furthermore, we identify a missense mutational hotspot region in the helicase domain. We also confirm that all three ATRX mutation types are more often identified in patients diagnosed at an older age, but still approximately 40% of the patients are aged 5 years or younger at diagnosis. Surprisingly, we found that 11q deletions are enriched in neuroblastomas with ATRX deletions compared to a reference cohort, but not in neuroblastomas with ATRX point mutations. Taken together, our data emphasizes a distinct ATRX mutation spectrum in neuroblastoma, which should be considered when studying molecular phenotypes and therapeutic strategies.


Assuntos
Neuroblastoma , Proteína Nuclear Ligada ao X , Cromatina , DNA Helicases/genética , Humanos , Mutação , Neuroblastoma/genética , Neuroblastoma/patologia , Fenótipo , Proteína Nuclear Ligada ao X/genética
9.
J Pediatr Hematol Oncol ; 44(1): e5-e13, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33885033

RESUMO

Refractory stage M neuroblastoma (NB) is associated with a poor prognosis and a progressive course of disease. Here, we describe a unique group of patients with a discrepant clinical course. Seven histologically confirmed ganglioneuroblastoma (GNB) (n=6) and differentiating NB (n=1) patients were identified who were diagnosed with stage M disease based on iodine-123-metaiodobenzylguanidine avid bone metastases. Six patients started on high-risk treatment, without tumor response (stable disease). Treatment was discontinued before the start of consolidation treatment because of refractory response in all patients. Unexpectedly, after cessation of treatment no progression of disease occurred. In 2 patients, the primary tumors expanded (>25%) very slowly during 1.5 and 3 years, and remained stable thereafter. Metabolically, a slow decrease of urinary homovanillic acid and vanillylmandelic acid levels and iodine-123-metaiodobenzylguanidine avidity was observed. All patients are alive with presence of metastatic disease after a median follow-up of 17 years (range: 6.7 to 27 y). Interestingly, at diagnosis, 6 patients were asymptomatic, 6 patients had GNB morphology, and 5 patients had meningeal metastases. These are all features seen in only a small minority of stage M patients. This GNB entity illustrates the clinical heterogeneity of neuroblastic tumors and can be used to further study the developmental origin of different NB subtypes.


Assuntos
Neoplasias Ósseas , Quimioterapia de Consolidação , Ganglioneuroblastoma , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias Ósseas/urina , Pré-Escolar , Doença Crônica , Feminino , Ganglioneuroblastoma/tratamento farmacológico , Ganglioneuroblastoma/urina , Humanos , Lactente , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Retrospectivos
10.
Pediatr Blood Cancer ; 67(4): e28061, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31736229

RESUMO

BACKGROUND: The clinical course of neuroblastoma stage 4S or MS is characterized by a high rate of spontaneous tumor regression and favorable outcome. However, the clinical course and rate of the regression are poorly understood. METHODS: A retrospective cohort study was performed, including all patients with stage 4S neuroblastoma without MYCN amplification, from two Dutch centers between 1972 and 2012. We investigated the clinical characteristics, the biochemical activity reflected in urinary catecholamine excretion, and radiological imaging to describe the kinetics of tumor regression, therapy response and outcome. RESULTS: The cohort of 31 patients reached a 10-year overall survival of 84% ± 7% (median follow-up 16 years; range, 3.3-39). During the regressive phase, liver size normalized in 91% of the patients and catecholamine excretion in 83%, both after a median of two months (liver size: range, 0-131; catecholamines: range, 0-158). The primary tumors completely regressed in 69% after 13 months (range, 6-73), and the liver architecture normalized in 52% after 15 months (range, 5-131). Antitumor treatment was given in 52% of the patients. Interestingly, regression rates were similar for treated and untreated patients. Four of seven patients < 4 weeks old died of rapid liver expansion and organ compression. Three patients progressed to stage 4, 3 to 13 months after diagnosis; all had persistently elevated catecholamines. CONCLUSION: Patients < 4 weeks old with neuroblastoma stage 4S are at risk of fatal outcome caused by progression of liver metastases. In other patients, tumor regression is characterized by a rapid biochemical normalization that precedes radiological regression.


Assuntos
Regressão Neoplásica Espontânea/patologia , Neuroblastoma/patologia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco
11.
Nature ; 483(7391): 589-93, 2012 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-22367537

RESUMO

Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.


Assuntos
Cromossomos Humanos/genética , Neuritos/metabolismo , Neuroblastoma/genética , Neuroblastoma/patologia , Envelhecimento/genética , Análise por Conglomerados , DNA Helicases/genética , Análise Mutacional de DNA , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Cones de Crescimento/metabolismo , Cones de Crescimento/patologia , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Mutação , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico , Neuroblastoma/metabolismo , Proteínas Nucleares/genética , Prognóstico , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T , Proteína Nuclear Ligada ao X , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo
12.
Lancet Oncol ; 18(7): e394-e404, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28677575

RESUMO

New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic-pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.


Assuntos
Antineoplásicos/uso terapêutico , Legislação de Medicamentos , Neoplasias/tratamento farmacológico , Medicina de Precisão , Adolescente , Antineoplásicos/farmacologia , Produtos Biológicos/uso terapêutico , Criança , Pré-Escolar , Descoberta de Drogas/legislação & jurisprudência , Europa (Continente) , Humanos , Lactente , Recém-Nascido
14.
Int J Cancer ; 136(6): 1308-20, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25046253

RESUMO

MicroRNAs (miRNAs) are deregulated in a variety of human cancers, including neuroblastoma, the most common extracranial tumor of childhood. We previously reported a signature of 42 miRNAs to be highly predictive of neuroblastoma outcome. One miRNA in this signature, miR-542, was downregulated in tumors from patients with adverse outcome. Reanalysis of quantitative PCR and next-generation sequencing transcript data revealed that miR-542-5p as well as miR-542-3p expression is inversely correlated with poor prognosis in neuroblastoma patients. We, therefore, analyzed the function of miR-542 in neuroblastoma tumor biology. Ectopic expression of miR-542-3p in neuroblastoma cell lines reduced cell viability and proliferation, induced apoptosis and downregulated Survivin. Survivin expression was also inversely correlated with miR-542-3p expression in primary neuroblastomas. Reporter assays confirmed that miR-542-3p directly targeted Survivin. Downregulating Survivin using siRNA copied the phenotype of miR-542-3p expression in neuroblastoma cell lines, while cDNA-mediated ectopic expression of Survivin partially rescued the phenotype induced by miR-542-3p expression. Treating nude mice bearing neuroblastoma xenografts with miR-542-3p-loaded nanoparticles repressed Survivin expression, decreased cell proliferation and induced apoptosis in the respective xenograft tumors. We conclude that miR-542-3p exerts its tumor suppressive function in neuroblastoma, at least in part, by targeting Survivin. Expression of miR-542-3p could be a promising therapeutic strategy for treating aggressive neuroblastoma.


Assuntos
Proteínas Inibidoras de Apoptose/fisiologia , MicroRNAs/fisiologia , Neuroblastoma/patologia , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Regulação para Baixo , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/genética , Masculino , Camundongos , Proteína Proto-Oncogênica N-Myc , Nanopartículas , Neuroblastoma/prevenção & controle , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Survivina
15.
Proc Natl Acad Sci U S A ; 109(47): 19190-5, 2012 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-23091029

RESUMO

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. MYCN (V-myc myelocytomatosis viral-related oncogene, neuroblastoma derived [avian]) is amplified in 20% of neuroblastomas, and these tumors carry a poor prognosis. However, tumors without MYCN amplification also may have a poor outcome. Here, we identified downstream targets of MYCN by shRNA-mediated silencing MYCN in neuroblastoma cells. From these targets, 157 genes showed an expression profile correlating with MYCN mRNA levels in NB88, a series of 88 neuroblastoma tumors, and therefore represent in vivo relevant MYCN pathway genes. This 157-gene signature identified very poor prognosis tumors in NB88 and independent neuroblastoma cohorts and was more powerful than MYCN amplification or MYCN expression alone. Remarkably, this signature also identified poor outcome of a group of tumors without MYCN amplification. Most of these tumors have low MYCN mRNA levels but high nuclear MYCN protein levels, suggesting stabilization of MYCN at the protein level. One tumor has an MYC amplification and high MYC expression. Chip-on-chip analyses showed that most genes in this signature are directly regulated by MYCN. MYCN induces genes functioning in cell cycle and DNA repair while repressing neuronal differentiation genes. The functional MYCN-157 signature recognizes classical neuroblastoma with MYCN amplification, as well as a newly identified group marked by MYCN protein stabilization.


Assuntos
Amplificação de Genes/genética , Perfilação da Expressão Gênica , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Diferenciação Celular/genética , Análise por Conglomerados , Reparo do DNA/genética , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos/genética , Humanos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/patologia , Neurônios/patologia , Proteínas Nucleares/metabolismo , Proteínas Oncogênicas/metabolismo , Prognóstico , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Resultado do Tratamento , Regulação para Cima/genética
16.
Curr Opin Oncol ; 26(1): 64-72, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24305569

RESUMO

PURPOSE OF REVIEW: A variety of mutational mechanisms shape the landscape of somatic mutations in cancer genomes. Although the contribution of single nucleotide mutations is well studied, getting a hold of structural genomic rearrangements is more difficult due to their complexity and diversity in sizes and classes. Here, we discuss the incidence of complex genomic rearrangements and their impact on cancer development and progression. RECENT FINDINGS: Catastrophic genome rearrangements have recently been described in various cancer genomes. Such complex genomic rearrangements may be a result of local shattering of chromosomes followed by reassembly of DNA fragments, a process termed chromothripsis. In addition, DNA replication errors may lead to complex genomic rearrangements in cancer. Complex reshuffling of chromosomes can cause formation of gene fusions, disruption of tumor suppressors, and amplification of oncogenes. Furthermore, the occurrence of chromothripsis has been associated with poor prognosis in neuroblastoma, melanoma, and multiple myeloma. SUMMARY: Complex genomic rearrangements, such as chromothripsis, may affect cancer gene function and thereby have a major impact on cancer progression, prognosis, and therapy response.


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Rearranjo Gênico , Neoplasias/genética , Progressão da Doença , Humanos
17.
Hemasphere ; 8(7): e122, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39011126

RESUMO

Over the past 10 years, institutional and national molecular tumor boards have been implemented for relapsed or refractory pediatric cancer to prioritize targeted drugs for individualized treatment based on actionable oncogenic lesions, including the Dutch iTHER platform. Hematological malignancies form a minority in precision medicine studies. Here, we report on 56 iTHER leukemia/lymphoma patients for which we considered cell surface markers and oncogenic aberrations as actionable events, supplemented with ex vivo drug sensitivity for six patients. Prior to iTHER registration, 34% of the patients had received allogeneic hematopoietic cell transplantation (HCT) and 18% CAR-T therapy. For 51 patients (91%), a sample with sufficient tumor percentage (≥20%) required for comprehensive diagnostic testing was obtained. Up to 10 oncogenic actionable events were prioritized in 49/51 patients, and immunotherapy targets were identified in all profiled patients. Targeted treatment(s) based on the iTHER advice was given to 24 of 51 patients (47%), including immunotherapy in 17 patients, a targeted drug matching an oncogenic aberration in 12 patients, and a drug based on ex vivo drug sensitivity in one patient, resulting in objective responses and a bridge to HCT in the majority of the patients. In conclusion, comprehensive profiling of relapsed/refractory hematological malignancies showed multiple oncogenic and immunotherapy targets for a precision medicine approach, which requires multidisciplinary expertise to prioritize the best treatment options for this rare, heavily pretreated pediatric population.

18.
Cell Genom ; : 100675, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39406233

RESUMO

In pediatric cancer, structural variants (SVs) and copy-number alterations contribute to cancer initiation as well as progression, thereby aiding diagnosis and treatment stratification. Although suggested to be of importance, the prevalence and biological relevance of complex genomic rearrangements (CGRs) across pediatric solid tumors is largely unexplored. In a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy, and chromothripsis across five pediatric solid cancer types. CGRs were identified in 56 tumors (47%), and in 42 of these tumors, CGRs affect cancer driver genes or result in unfavorable chromosomal alterations. This demonstrates that CGRs are prevalent and pathogenic in pediatric solid tumors and suggests that selection likely contributes to the structural variation landscape. Moreover, carrying CGRs is associated with more adverse clinical events. Our study highlights the potential for CGRs to be incorporated in risk stratification or exploited for targeted treatments.

19.
EMBO Mol Med ; 16(7): 1495-1514, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38831131

RESUMO

Achieving complete tumor resection is challenging and can be improved by real-time fluorescence-guided surgery with molecular-targeted probes. However, pre-clinical identification and validation of probes presents a lengthy process that is traditionally performed in animal models and further hampered by inter- and intra-tumoral heterogeneity in target expression. To screen multiple probes at patient scale, we developed a multispectral real-time 3D imaging platform that implements organoid technology to effectively model patient tumor heterogeneity and, importantly, healthy human tissue binding.


Assuntos
Imageamento Tridimensional , Organoides , Humanos , Imageamento Tridimensional/métodos , Cirurgia Assistida por Computador/métodos , Imagem Óptica/métodos , Animais , Neoplasias/cirurgia , Corantes Fluorescentes/química
20.
Cancer Cell ; 42(2): 283-300.e8, 2024 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-38181797

RESUMO

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations. NK cells show reduced cytotoxicity and T cells have a dysfunctional profile. Interaction analysis reveals a vast immunoregulatory network and identifies NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduces neuroblastoma growth, with complete responses (CR) in vivo. Moreover, addition of TIGIT+PD-L1 blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.


Assuntos
Antígeno B7-H1 , Neuroblastoma , Humanos , Criança , Recidiva Local de Neoplasia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Receptores Imunológicos/genética , Imunoterapia , Análise de Sequência de RNA
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