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1.
Pediatr Blood Cancer ; 66(10): e27897, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250523

RESUMO

We report two patients with leukaemia driven by the rare CNTRL-FGFR1 fusion oncogene. This fusion arises from a t(8;9)(p12;q33) translocation, and is a rare driver of biphenotypic leukaemia in children. We used RNA sequencing to report novel features of expressed CNTRL-FGFR1, including CNTRL-FGFR1 fusion alternative splicing. From this knowledge, we designed and tested a Droplet Digital PCR assay that detects CNTRL-FGFR1 expression to approximately one cell in 100 000 using fusion breakpoint-specific primers and probes. We also utilised cell-line models to show that effective tyrosine kinase inhibitors, which may be included in treatment regimens for this disease, are only those that block FGFR1 phosphorylation.

2.
Nat Genet ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429576

RESUMO

In the version of this article originally published, the main-text sentence "In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor" misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper.

3.
Nat Genet ; 50(12): 1650-1657, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30374066

RESUMO

Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.

4.
Br J Cancer ; 119(6): 693-696, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30220707

RESUMO

Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG). TRK fusions have a critical role in tumourigenesis in 40% of infant HGG. Here we report the first case of a TRK fusion-driven HGG treated with larotrectinib-the first selective pan-TRK inhibitor in clinical development. This 3-year-old girl had failed multiple therapies including chemotherapy and radiotherapy. Tumour profiling confirmed an ETV6-NTRK3 fusion. Treatment with larotrectinib led to rapid clinical improvement with near total resolution of primary and metastatic lesions on MRI imaging. This is the first report of a TRK fusion glioma successfully treated with a TRK inhibitor.

5.
Cancer Cell ; 30(6): 891-908, 2016 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-27960086

RESUMO

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Cromatina/genética , Epigenômica/métodos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Metilação de DNA , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Humanos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Tumor Rabdoide/tratamento farmacológico , Teratoma/tratamento farmacológico
6.
Oncotarget ; 6(31): 31844-56, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26378811

RESUMO

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.


Assuntos
Aneuploidia , Astrocitoma/classificação , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/classificação , Adulto , Fatores Etários , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Mutação/genética , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
7.
Acta Neuropathol ; 125(5): 659-69, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23417712

RESUMO

Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15% of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15% of pediatric HGGs (11/73) and 8% of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Mutação/genética , Adolescente , Adulto , Fatores Etários , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Exoma , Glioma/metabolismo , Glioma/patologia , Histona Metiltransferases , Humanos , Lactente , Metilação , Pessoa de Meia-Idade , Gradação de Tumores , Adulto Jovem
8.
Pediatrics ; 131(2): e620-5, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23319530

RESUMO

Iron-refractory iron-deficiency anemia (IRIDA) is an autosomal recessive disorder caused by mutations in TMPRSS6. Patients have hypochromic microcytic anemia refractory to oral iron and are only partially responsive to parenteral iron administration. We report a French-Canadian kindred in which 2 siblings presented in early childhood with severe microcytic anemia, hypoferremia, and hyperferritinemia. Both children have been successfully treated solely with low-dose oral iron since diagnosis. Clinical and biological presentation did not fit any previously described genetic iron-deficiency anemia. Whole exome sequencing identified in both patients compound heterozygous mutations of TMPRSS6 leading to p.G442R and p.E522K, 2 mutations previously reported to cause classic IRIDA, and no additional mutations in known iron-regulatory genes. Thus, the phenotype associated with the unique combination of mutations uncovered in both patients expands the spectrum of disease associated with TMPRSS6 mutations to include iron deficiency anemia that is accompanied by hyperferritinemia at initial presentation and is responsive to continued oral iron therapy. Our results have implications for genetic testing in early childhood iron deficiency anemia. Importantly, they emphasize that whole exome sequencing can be used as a diagnostic tool and greatly facilitate the elucidation of the genetic basis of unusual clinical presentations, including hypomorphic mutations or compound heterozygosity leading to different phenotypes in known Mendelian diseases.


Assuntos
Anemia Hipocrômica/tratamento farmacológico , Anemia Hipocrômica/genética , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/genética , Anemia Refratária/tratamento farmacológico , Anemia Refratária/genética , Aberrações Cromossômicas , Análise Mutacional de DNA , Ferritinas/sangue , Ferro/administração & dosagem , Proteínas de Membrana/genética , Serina Endopeptidases/genética , Administração Oral , Adolescente , Anemia Hipocrômica/diagnóstico , Anemia Ferropriva/diagnóstico , Anemia Refratária/diagnóstico , Criança , Pré-Escolar , Exoma/genética , Feminino , Seguimentos , Triagem de Portadores Genéticos , Genótipo , Humanos , Assistência de Longa Duração , Masculino , Mutação de Sentido Incorreto
9.
Cancer Cell ; 22(4): 425-37, 2012 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-23079654

RESUMO

Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.


Assuntos
Neoplasias Encefálicas/genética , Epigênese Genética , Glioblastoma/genética , Histonas/genética , Isocitrato Desidrogenase/genética , Mutação , Adulto , Neoplasias Encefálicas/patologia , Criança , Metilação de DNA , Glioblastoma/patologia , Humanos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Transcriptoma
11.
Acta Neuropathol ; 124(5): 615-25, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22886134

RESUMO

Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p < 0.0001) and TP53 (p < 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p < 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , DNA Helicases/genética , Regulação Neoplásica da Expressão Gênica/genética , Mutação/genética , Proteínas Nucleares/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Astrocitoma/classificação , Astrocitoma/patologia , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Feminino , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , RNA Mensageiro/metabolismo , Proteína Nuclear Ligada ao X , Adulto Jovem
12.
Acta Neuropathol ; 124(3): 439-47, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22661320

RESUMO

Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.


Assuntos
Neoplasias do Tronco Encefálico/genética , Glioma/genética , Histonas/genética , Ponte/patologia , Adolescente , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Glioma/mortalidade , Glioma/patologia , Humanos , Lactente , Masculino , Mutação , Prognóstico , Taxa de Sobrevida
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