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2.
Haematologica ; 108(2): 543-554, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35522148

RESUMO

Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.


Assuntos
Linfoma de Células B , Linfoma , Humanos , Histonas/metabolismo , Histona Desmetilases/genética , Homozigoto , Deleção de Sequência , Linfoma/genética , Linfoma de Células B/genética , Sequenciamento Completo do Genoma , RNA , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/química , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona-Lisina N-Metiltransferase/genética
4.
Nat Commun ; 13(1): 2558, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538064

RESUMO

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations.


Assuntos
Neoplasias do Sistema Nervoso Central , Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Genômica , Herpesvirus Humano 4 , Humanos , Linfoma Difuso de Grandes Células B/metabolismo
5.
Genes Chromosomes Cancer ; 61(7): 432-436, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35218115

RESUMO

Deregulation of micro(mi)-RNAs is a common mechanism in tumorigenesis. We investigated the expression of 2083 miRNAs in T-cell prolymphocytic leukemia (T-PLL). Compared to physiologic CD4+ and CD8+ T-cell subsets, 111 miRNAs were differentially expressed in T-PLL. Of these, 33 belonged to miRNA gene clusters linked to cancer. Genomic variants affecting miRNAs were infrequent with the notable exception of copy number aberrations. Remarkably, we found strong upregulation of the miR-200c/-141 cluster in T-PLL to be associated with DNA hypomethylation and active promoter marks. Our findings suggest that copy number aberrations and epigenetic changes could contribute to miRNA deregulation in T-PLL.


Assuntos
Leucemia Prolinfocítica de Células T , MicroRNAs , Carcinogênese/genética , Metilação de DNA/genética , Epigênese Genética , Humanos , Leucemia Prolinfocítica de Células T/genética , MicroRNAs/genética
6.
Haematologica ; 107(8): 1891-1901, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35045690

RESUMO

The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms of resistance and potential therapeutic targets. We observed a high mutational load and indications of increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only observed at a lower frequency in newly diagnosed MM, included NRAS, BRAF, TP53, SLC4A7, MLLT4, EWSR1, HCFC2, and COPS3. We found multiple genomic regions with bi-allelic events affecting tumor suppressor genes and demonstrated a significant adverse impact of bi-allelic TP53 alterations on survival. With regard to potentially resistance conferring mutations, recurrently mutated gene networks included genes with relevance for PI and IMiD activity; the latter particularly affecting members of the Cereblon and the COP9 signalosome complex. We observed a major impact of signatures associated with exposure to melphalan or impaired DNA double-strand break homologous recombination repair in RRMM. The latter coincided with mutations in genes associated with PARP inhibitor sensitivity in 49% of RRMM patients; a finding with potential therapeutic implications. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies.


Assuntos
Mieloma Múltiplo , Resistencia a Medicamentos Antineoplásicos/genética , Genômica , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mutação , Inibidores de Proteassoma/uso terapêutico
7.
J Clin Oncol ; 39(29): 3217-3228, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34110923

RESUMO

PURPOSE: Clinical outcomes of patients with neuroblastoma range from spontaneous tumor regression to fatality. Hence, understanding the mechanisms that cause tumor progression is crucial for the treatment of patients. In this study, we show that FOXR2 activation identifies a subset of neuroblastoma tumors with unfavorable outcome and we investigate the mechanism how FOXR2 relates to poor outcome in patients. MATERIALS AND METHODS: We analyzed three independent transcriptional data sets of in total 1030 primary neuroblastomas with full clinical annotation. We performed immunoprecipitation for FOXR2 and MYCN and silenced FOXR2 expression in two neuroblastoma cell lines to examine the effect on cellular processes, transcriptome, and MYCN protein levels. Tumor samples were analyzed for protein levels of FOXR2 and MYCN. RESULTS: In three combined neuroblastoma data sets, 9% of tumors show expression of FOXR2 but have low levels of MYCN mRNA. FOXR2 expression identifies a group of patients with unfavorable outcome, showing 10-year overall survival rates of 53%-59%, and proves to be an independent prognostic factor compared with established risk factors. Transcriptionally, FOXR2-expressing tumors are very similar to MYCN-amplified tumors, suggesting that they might share a common mechanism of tumor initiation. FOXR2 knockdown in FOXR2-expressing neuroblastoma cell lines resulted in cell cycle arrest, reduced cell growth, cell death, and reduced MYCN protein levels, all indicating that FOXR2 is essential for these tumors. Finally, we show that FOXR2 binds and stabilizes MYCN protein and MYCN protein levels are highly increased in FOXR2-expressing tumors, in several cases comparable with MYCN-amplified samples. CONCLUSION: The stabilization of MYCN by FOXR2 represents an alternative mechanism to MYCN amplification to increase MYCN protein levels. As such, FOXR2 expression identifies another subset of neuroblastoma patients with unfavorable clinical outcome.


Assuntos
Fatores de Transcrição Forkhead/fisiologia , Amplificação de Genes , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/mortalidade , Linhagem Celular Tumoral , Humanos , Proteína Proto-Oncogênica N-Myc/química , Neuroblastoma/genética , Neuroblastoma/patologia , Prognóstico , Estabilidade Proteica , Telomerase/genética
8.
Leukemia ; 35(7): 2002-2016, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33953289

RESUMO

B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR. We show that not only SHM, but presumably also CSR causes off-target mutations in non-IG genes. Kataegis clusters with high mutational density mainly affected early replicating regions and were enriched for SHM- and CSR-mediated off-target mutations. Moreover, they often co-occurred in loci physically interacting in the nucleus, suggesting that mutation hotspots promote increased mutation targeting of spatially co-localized loci (termed hypermutation by proxy). Only around 1% of somatic small variants were in protein coding sequences, but in about half of the driver genes, a contribution of B-cell specific mutational processes to their mutations was found. The B-cell-specific mutational processes contribute to both lymphoma initiation and intratumoral heterogeneity. Overall, we demonstrate that mutational processes involved in the development of gcBCL are more complex than previously appreciated, and that B cell-specific mutational processes contribute via diverse mechanisms to lymphomagenesis.


Assuntos
Genoma/genética , Centro Germinativo/metabolismo , Linfoma de Células B/genética , Mutação/genética , Adulto , Linfócitos B/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Genes de Imunoglobulinas/genética , Células HeLa , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Switching de Imunoglobulina/genética , Células K562 , Células MCF-7 , Hipermutação Somática de Imunoglobulina/genética , Recombinação V(D)J/genética
9.
Life Sci Alliance ; 4(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33658318

RESUMO

The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin-GEF1-suppressed ADRN-type cells are a batch of AU-rich element-containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis-based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neuroblastoma/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Neurônios Adrenérgicos/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Células Cultivadas , Pré-Escolar , Bases de Dados Genéticas , Feminino , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Humanos , Masculino , Neuroblastoma/patologia , Estudos Prospectivos , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas rac1 de Ligação ao GTP/fisiologia
10.
Nat Genet ; 53(5): 683-693, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33767450

RESUMO

Neuroblastoma is a pediatric tumor of the developing sympathetic nervous system. However, the cellular origin of neuroblastoma has yet to be defined. Here we studied the single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development. We defined normal differentiation trajectories from Schwann cell precursors over intermediate states to neuroblasts or chromaffin cells and showed that neuroblastomas transcriptionally resemble normal fetal adrenal neuroblasts. Importantly, neuroblastomas with varying clinical phenotypes matched different temporal states along normal neuroblast differentiation trajectories, with the degree of differentiation corresponding to clinical prognosis. Our work highlights the roles of oncogenic MYCN and loss of TFAP2B in blocking differentiation and may provide the basis for designing therapeutic interventions to overcome differentiation blocks.


Assuntos
Perfilação da Expressão Gênica , Neuroblastoma/genética , Neuroblastoma/patologia , Análise de Célula Única , Glândulas Suprarrenais/embriologia , Glândulas Suprarrenais/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Transcriptoma/genética , Resultado do Tratamento
11.
Nat Commun ; 12(1): 1269, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627664

RESUMO

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.


Assuntos
Sequenciamento Completo do Genoma/métodos , Western Blotting , Éxons/genética , Citometria de Fluxo , Humanos , Proteoma/metabolismo , Estudos Retrospectivos , Análise de Sequência de RNA/métodos , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero/genética , Proteína Nuclear Ligada ao X/genética
12.
Genome Res ; 31(3): 448-460, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33441414

RESUMO

The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples (n = 803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with KRAS wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in KRAS In addition, we confirmed the transforming potential of two novel fusions, RRBP1-RAF1 and RASGRP1-ATP1A1, in cellular assays. These results show Arriba's utility in both basic cancer research and clinical translation.


Assuntos
Fusão Gênica/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias Pancreáticas/genética , RNA/genética , Análise de Sequência de RNA , Humanos , Medicina de Precisão , Proteínas Proto-Oncogênicas/genética
13.
Nat Cancer ; 2(1): 114-128, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-35121888

RESUMO

Half of the children diagnosed with neuroblastoma (NB) have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from NB are lacking. Here, using genome-wide H3K27ac profiles across 60 NBs, covering the different clinical and molecular subtypes, we identified four major super-enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups; namely, MYCN-amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk NBs. The fourth subtype, exhibiting mesenchymal characteristics, shared cellular identity with multipotent Schwann cell precursors, was induced by RAS activation and was enriched in relapsed disease. Notably, CCND1, an essential gene in NB, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Overall, this study reveals subtype-specific super-enhancer regulation in NBs.


Assuntos
Neuroblastoma , Criança , Humanos , Mutação , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Sequências Reguladoras de Ácido Nucleico
14.
Nat Commun ; 11(1): 5414, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110075

RESUMO

The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.


Assuntos
Neoplasias Ósseas/genética , Tumor de Células Gigantes do Osso/genética , Histonas/genética , Osteogênese , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/fisiopatologia , Metilação de DNA , Epigênese Genética , Epigenômica , Tumor de Células Gigantes do Osso/metabolismo , Tumor de Células Gigantes do Osso/fisiopatologia , Histonas/metabolismo , Humanos , Mutação de Sentido Incorreto
15.
EBioMedicine ; 59: 102971, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32846370

RESUMO

BACKGROUND: In neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research. METHODS: To evaluate the impact of ATRX loss of function (LoF) in neuroblastoma, we utilized CRISPR-Cas9 gene editing to generate neuroblastoma cell lines isogenic for ATRX. We used these and other models to identify therapeutically exploitable synthetic lethal vulnerabilities associated with ATRX LoF. FINDINGS: In isogenic cell lines, we found that ATRX inactivation results in increased DNA damage, homologous recombination repair (HRR) defects and impaired replication fork processivity. In keeping with this, high-throughput compound screening showed selective sensitivity in ATRX mutant cells to multiple PARP inhibitors and the ATM inhibitor KU60019. ATRX mutant cells also showed selective sensitivity to the DNA damaging agents, sapacitabine and irinotecan. HRR deficiency was also seen in the ATRX deleted CHLA-90 cell line, and significant sensitivity demonstrated to olaparib/irinotecan combination therapy in all ATRX LoF models. In-vivo sensitivity to olaparib/irinotecan was seen in ATRX mutant but not wild-type xenografts. Finally, sustained responses to olaparib/irinotecan therapy were seen in an ATRX deleted neuroblastoma patient derived xenograft. INTERPRETATION: ATRX LoF results in specific DNA damage repair defects that can be therapeutically exploited. In ATRX LoF models, preclinical sensitivity is demonstrated to olaparib and irinotecan, a combination that can be rapidly translated into the clinic. FUNDING: This work was supported by Christopher's Smile, Neuroblastoma UK, Cancer Research UK, and the Royal Marsden Hospital NIHR BRC.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Neuroblastoma/genética , Proteína Nuclear Ligada ao X/genética , Animais , Antineoplásicos/uso terapêutico , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Modelos Animais de Doenças , Edição de Genes , Técnicas de Inativação de Genes , Humanos , Imuno-Histoquímica , Camundongos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Genes Chromosomes Cancer ; 59(4): 261-267, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31677197

RESUMO

T-cell prolymphocytic leukemia (T-PLL) is an aggressive tumor with leukemic presentation of mature T-lymphocytes. Here, we aimed at characterizing the initial events in the molecular pathogenesis of T-PLL and particularly, at determining the point in T-cell differentiation when the hallmark oncogenic events, that is, inv(14)(q11q32)/t(14;14)(q11;q32) and t(X;14)(q28;q11) occur. To this end, we mined whole genome and transcriptome sequencing data of 17 and 11 T-PLL cases, respectively. Mapping of the 14q32.1 locus breakpoints identified only TCL1A, which was moreover significantly overexpressed in T-PLL as compared to benign CD4+ and CD8+ T-cells, as the only common oncogenic target of aberrations. In cases with t(14;14), the breakpoints mapped telomeric and in cases with inv(14) centromeric or in the 3'-untranslated region of TCL1A. Regarding the T-cell receptor alpha (TRA) locus-TCL1A breakpoint junctions, all 17 breakpoints involved recombination signal sequences and 15 junctions contained nontemplated (N-) nucleotides. All T-PLL cases studied carried in-frame TRA rearrangements on the intact allele, which skewed significantly toward usage of distal/central TRAV/TRAJ gene segments as compared to the illegitimate TRA rearrangements. Our findings suggest that the oncogenic TRA-TCL1A/MTCP1 rearrangements in T-PLL occur during opening of the TRA locus, that is, during the progression from CD4+ immature single positive to early double positive thymocyte stage, just before physiologic TCL1A expression is silenced. The cell carrying such an oncogenic event continues maturation and rearranges the second TRA allele to achieve a functional T-cell receptor. Thereafter, it switches off RAG and DNTT expression in line with the mature T-cell phenotype at presentation of T-PLL.


Assuntos
Rearranjo Gênico , Predisposição Genética para Doença , Leucemia Prolinfocítica de Células T/genética , Receptores de Antígenos de Linfócitos T/genética , Transcriptoma , Sequenciamento Completo do Genoma , Alelos , Aberrações Cromossômicas , Estudo de Associação Genômica Ampla , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico , Proteínas de Fusão Oncogênica/genética , Fenótipo
18.
Acta Neuropathol ; 138(2): 295-308, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31069492

RESUMO

DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1-3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.


Assuntos
Metilação de DNA , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Meníngeas/classificação , Meningioma/classificação , Mutação , Imunoprecipitação da Cromatina , Dosagem de Genes , Instabilidade Genômica , Humanos , Neoplasias Meníngeas/etiologia , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meningioma/etiologia , Meningioma/genética , Meningioma/patologia , Proteínas de Neoplasias/genética , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/patologia , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Neoplásico/genética , Reparo de DNA por Recombinação , Alinhamento de Sequência , Fatores de Transcrição/fisiologia , Transcriptoma , Sequenciamento Completo do Genoma
19.
Nat Commun ; 10(1): 1459, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926794

RESUMO

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.


Assuntos
Linfoma de Burkitt/genética , Genoma Humano , Transcriptoma/genética , Adolescente , Processamento Alternativo/genética , Sequência de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Estudos de Coortes , Metilação de DNA/genética , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação INDEL/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fases de Leitura Aberta/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética , Sequenciamento Completo do Genoma
20.
Nat Commun ; 9(1): 4782, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429477

RESUMO

Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3' UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3' UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Neoplasias Hepáticas/genética , Medicina de Precisão , Regiões 3' não Traduzidas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/secundário , Idoso , Anoctaminas/genética , Proteínas Reguladoras de Apoptose , Proteína BRCA2/genética , Adesão Celular/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Proteínas de Ligação a DNA , Matriz Extracelular/genética , Feminino , Fatores de Transcrição Forkhead/genética , Células Estreladas do Fígado/metabolismo , Humanos , Neoplasias Hepáticas/secundário , Masculino , Proteínas de Membrana , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-cbl/genética , RNA não Traduzido , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Transdução de Sinais , Canais de Cátion TRPM/genética , Fatores de Transcrição/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Sequenciamento Completo do Genoma
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