RESUMO
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of multiple cysts in the kidneys. It is often caused by pathogenic mutations in PKD1 and PKD2 genes that encode polycystin proteins. Although the molecular mechanisms for cystogenesis are not established, concurrent inactivating germline and somatic mutations in PKD1 and PKD2 have been previously observed in renal tubular epithelium (RTE). METHODS: To further investigate the cellular recessive mechanism of cystogenesis in RTE, we conducted whole-genome DNA sequencing analysis to identify germline variants and somatic alterations in RTE of 90 unique kidney cysts obtained during nephrectomy from 24 unrelated participants. RESULTS: Kidney cysts were overall genomically stable, with low burdens of somatic short mutations or large-scale structural alterations. Pathogenic somatic "second hit" alterations disrupting PKD1 or PKD2 were identified in 93% of the cysts. Of these, 77% of cysts acquired short mutations in PKD1 or PKD2 ; specifically, 60% resulted in protein truncations (nonsense, frameshift, or splice site) and 17% caused non-truncating mutations (missense, in-frame insertions, or deletions). Another 18% of cysts acquired somatic chromosomal loss of heterozygosity (LOH) events encompassing PKD1 or PKD2 ranging from 2.6 to 81.3 Mb. 14% of these cysts harbored copy number neutral LOH events, while the other 3% had hemizygous chromosomal deletions. LOH events frequently occurred at chromosomal fragile sites, or in regions comprising chromosome microdeletion diseases/syndromes. Almost all somatic "second hit" alterations occurred at the same germline mutated PKD1/2 gene. CONCLUSIONS: These findings further support a cellular recessive mechanism for cystogenesis in ADPKD primarily caused by inactivating germline and somatic variants of PKD1 or PKD2 genes in kidney cyst epithelium.
Assuntos
Cistos , Rim Policístico Autossômico Dominante , Humanos , Rim Policístico Autossômico Dominante/genética , Mutação , Células Epiteliais , Canais de Cátion TRPP/genéticaRESUMO
Receptor tyrosine kinases (RTKs) are a class of cell surface receptors that, upon ligand binding, stimulate a variety of critical cellular functions. The orphan receptor anaplastic lymphoma kinase (ALK) is one of very few RTKs that remain without a firmly established protein ligand. Here we present a novel cytokine, FAM150B, which we propose naming augmentor-α (AUG-α), as a ligand for ALK. AUG-α binds ALK with high affinity and activates ALK in cells with subnanomolar potency. Detailed binding experiments using cells expressing ALK or the related receptor leukocyte tyrosine kinase (LTK) demonstrate that AUG-α binds and robustly activates both ALK and LTK. We show that the previously established LTK ligand FAM150A (AUG-ß) is specific for LTK and only weakly binds to ALK. Furthermore, expression of AUG-α stimulates transformation of NIH/3T3 cells expressing ALK, induces IL-3 independent growth of Ba/F3 cells expressing ALK, and is expressed in neuroblastoma, a cancer partly driven by ALK. These experiments reveal the hierarchy and specificity of two cytokines as ligands for ALK and LTK and set the stage for elucidating their roles in development and disease states.
Assuntos
Citocinas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Sequência de Aminoácidos , Quinase do Linfoma Anaplásico , Animais , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Citocinas/genética , Doxiciclina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Heparina/farmacologia , Humanos , Immunoblotting , Ligantes , Camundongos , Dados de Sequência Molecular , Células NIH 3T3 , Ligação Proteica , Receptores Proteína Tirosina Quinases/genética , Homologia de Sequência de AminoácidosRESUMO
The identification of cancer subtypes plays a very important role in the field of medicine. Accurate identification of cancer subtypes is helpful for both cancer treatment and prognosis Currently, most methods for cancer subtype identification are based on single-omics data, such as gene expression data. However, multi-omics data can show various characteristics about cancer, which also can improve the accuracy of cancer subtype identification. Therefore, how to extract features from multi-omics data for cancer subtype identification is the main challenge currently faced by researchers. In this paper, we propose a cancer subtype identification method named CAEM-GBDT, which takes gene expression data, miRNA expression data, and DNA methylation data as input, and adopts convolutional autoencoder network to identify cancer subtypes. Through a convolutional encoder layer, the method performs feature extraction on the input data. Within the convolutional encoder layer, a convolutional self-attention module is embedded to recognize higher-level representations of the multi-omics data. The extracted high-level representations from the convolutional encoder are then concatenated with the input to the decoder. The GBDT (Gradient Boosting Decision Tree) is utilized for cancer subtype identification. In the experiments, we compare CAEM-GBDT with existing cancer subtype identifying methods. Experimental results demonstrate that the proposed CAEM-GBDT outperforms other methods. The source code is available from GitHub at https://github.com/gxh-1/CAEM-GBDT.git.
RESUMO
PREMISE OF THE STUDY: Lateral roots, responsible for water and nutrient uptake, maintain nonvertical angles throughout development. Soil phosphate is one limiting nutrient for plant growth that is known to induce changes to root system architecture, such as increased lateral root formation. This study seeks to determine whether phosphate concentration affects lateral root orientation in addition to its previously described influences on root architecture. METHODS: Images of intact Arabidopsis root systems were recorded for 24 h, and lateral root tip angles were measured for wild-type and mutant pgm-1 and pin3-1 roots on a full or low phosphate medium. Setpoint angles of unstimulated root systems were determined, as were gravitropic responses of lateral roots over time. KEY RESULTS: The root system setpoint angles of wild-type and mutant pin3-1 roots showed a shift toward a more vertical orientation on low orthophosphate (Pi) medium. The gravitropic responses of both pgm-1 and pin3-1 roots on low Pi medium was elevated relative to control Pi medium. Mutations in two phosphate transporters with high levels of expression in the root showed a gravitropic response similar to wild-type roots grown on low Pi, supporting a role for Pi status in regulating lateral root gravitropism. CONCLUSIONS: Lateral root orientation and gravitropism are affected by Pi status and may provide an important additional parameter for describing root responses to low Pi. The data also support the conclusion that gravitropic setpoint angle reacts to nutrient status and is under dynamic regulation.
Assuntos
Arabidopsis/fisiologia , Gravitropismo/fisiologia , Fosfatos/farmacologia , Raízes de Plantas/fisiologia , Arabidopsis/efeitos dos fármacos , Gravitropismo/efeitos dos fármacos , Mutação/genética , Raízes de Plantas/efeitos dos fármacosRESUMO
This corrects the article DOI: 10.1038/ncomms14433.
RESUMO
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.
Assuntos
Glioma/tratamento farmacológico , Glutaratos/farmacologia , Recombinação Homóloga , Isocitrato Desidrogenase/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Animais , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Feminino , Glioma/genética , Humanos , Isocitrato Desidrogenase/farmacologia , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.
Assuntos
Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Genoma , Genômica/métodos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/metabolismo , Meningioma/genética , Meningioma/metabolismo , Sítios de Ligação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Transformação Celular Neoplásica/genética , Instabilidade Cromossômica , Análise por Conglomerados , Metilação de DNA , Fator de Transcrição E2F2/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigenômica/métodos , Exoma/genética , Proteína Forkhead Box M1/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genes da Neurofibromatose 2 , Técnicas de Genotipagem , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Técnicas de Sonda Molecular , Mutação , Fenótipo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Proteína SMARCB1/genética , Análise de Sequência , Transdução de Sinais/genética , TranscriptomaRESUMO
OBJECTIVE: Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells. METHODS: We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice. RESULTS: Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1(+/-) mice were protected against bleomycin-induced lung fibrosis and fibrocyte accumulation. CONCLUSION: Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin-1-dependent pathway. Netrin-1 regulates bleomycin-induced pulmonary fibrosis in mice. Netrin-1 might be a novel therapeutic target in SSc-related ILD.
Assuntos
Doenças Pulmonares Intersticiais/metabolismo , Pulmão/metabolismo , Fatores de Crescimento Neural/metabolismo , Fibrose Pulmonar/metabolismo , Escleroderma Sistêmico/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Anticorpos Neutralizantes/farmacologia , Fenômenos Biomecânicos , Bleomicina/toxicidade , Estudos de Casos e Controles , Diferenciação Celular , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Fibrose , Citometria de Fluxo , Imunofluorescência , Heterozigoto , Humanos , Antígenos Comuns de Leucócito/metabolismo , Leucócitos Mononucleares , Pulmão/efeitos dos fármacos , Pulmão/patologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Varredura , Fatores de Crescimento Neural/antagonistas & inibidores , Fatores de Crescimento Neural/genética , Netrina-1 , Proteômica , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Escleroderma Sistêmico/complicações , Alicerces Teciduais , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genéticaRESUMO
The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17-16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94-27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association.
Assuntos
Biomarcadores Tumorais/genética , Estudos de Associação Genética , Glioma/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Alelos , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteômica , Análise de Sequência de RNARESUMO
Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Neoplasias do Sistema Nervoso Central/patologia , Metilação de DNA , Células-Tronco Embrionárias/metabolismo , Proteína Forkhead Box M1 , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Genes myc , Glioma/patologia , Humanos , Isocitrato Desidrogenase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismoRESUMO
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.
Assuntos
Neoplasias Meníngeas/genética , Meningioma/genética , Mutação , RNA Polimerase II/genética , Domínio Catalítico/genética , Cromossomos Humanos Par 22 , Estudos de Coortes , Análise Mutacional de DNA , Elementos Facilitadores Genéticos , Exoma , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Meníngeas/classificação , Meningioma/classificação , Neurofibromina 2/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genéticaRESUMO
We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
Assuntos
Neoplasias Encefálicas/genética , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptores Acoplados a Proteínas G/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 22/genética , Análise Mutacional de DNA , Feminino , Genes da Neurofibromatose 2 , Instabilidade Genômica , Genômica , Humanos , Fator 4 Semelhante a Kruppel , Masculino , Neoplasias Meníngeas/classificação , Neoplasias Meníngeas/patologia , Meningioma/classificação , Meningioma/patologia , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Receptor SmoothenedRESUMO
The majority of understanding of root gravity responses comes from the study of primary roots, even though lateral roots make a far greater contribution to root system architecture. The focus of this report is the analysis of gravitropic responses in lateral roots of wild-type background and pgm-1 mutants. Despite the significant reduction in gravitropic response of primary roots of pgm-1 mutants, the lateral roots of this mutant demonstrate wild-type rates of gravitropism, suggesting a significant difference in gravity signal transduction between primary and lateral roots.