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1.
Nucleic Acids Res ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32083660

RESUMO

Measuring minimal residual disease in cancer has applications for prognosis, monitoring treatment and detection of recurrence. Simple sequence-based methods to detect nucleotide substitution variants have error rates (about 10-3) that limit sensitive detection. We developed and characterized the performance of MASQ (multiplex accurate sensitive quantitation), a method with an error rate below 10-6. MASQ counts variant templates accurately in the presence of millions of host genomes by using tags to identify each template and demanding consensus over multiple reads. Since the MASQ protocol multiplexes 50 target loci, we can both integrate signal from multiple variants and capture subclonal response to treatment. Compared to existing methods for variant detection, MASQ achieves an excellent combination of sensitivity, specificity and yield. We tested MASQ in a pilot study in acute myeloid leukemia (AML) patients who entered complete remission. We detect leukemic variants in the blood and bone marrow samples of all five patients, after induction therapy, at levels ranging from 10-2 to nearly 10-6. We observe evidence of sub-clonal structure and find higher target variant frequencies in patients who go on to relapse, demonstrating the potential for MASQ to quantify residual disease in AML.

2.
Nat Med ; 26(1): 143-150, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31873310

RESUMO

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

4.
Cell ; 171(2): 481-494.e15, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28985567

RESUMO

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.


Assuntos
Sistemas CRISPR-Cas , Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Células Cultivadas , Exoma , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Rituximab/administração & dosagem
5.
J Exp Med ; 214(5): 1371-1386, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28424246

RESUMO

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.


Assuntos
Linfoma de Células T Associado a Enteropatia/fisiopatologia , Histona-Lisina N-Metiltransferase/fisiologia , Animais , Variações do Número de Cópias de DNA/genética , Linfoma de Células T Associado a Enteropatia/classificação , Linfoma de Células T Associado a Enteropatia/genética , Feminino , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Mutação/genética , Análise de Sequência de DNA , Linfócitos T/fisiologia
6.
Biol Blood Marrow Transplant ; 23(6): 897-905, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28257800

RESUMO

Mesenchymal stem cells (MSCs) have immunosuppressive and tissue repair properties, but clinical trials using MSCs to prevent or treat graft-versus-host disease (GVHD) have shown mixed results. Macrophages (MØs) are important regulators of immunity and can promote tissue regeneration and remodeling. We have previously shown that MSCs can educate MØs toward a unique anti-inflammatory immunophenotype (MSC-educated MØs [MEMs]); however, their implications for in vivo models of inflammation have not been studied yet. We now show that in comparison with MØs, MEMs have increased expression of the inhibitory molecules PD-L1, PD-L2, in addition to markers of alternatively activated MØs: CD206 and CD163. RNA-Seq analysis of MEMs, as compared with MØs, show a distinct gene expression profile that positively correlates with multiple pathways important in tissue repair. MEMs also show increased expression of IL-6, transforming growth factor-ß, arginase-1, CD73, and decreased expression of IL-12 and tumor necrosis factor-α. We show that IL-6 secretion is controlled in part by the cyclo-oxygenase-2, arginase, and JAK1/STAT1 pathway. When tested in vivo, we show that human MEMs significantly enhance survival from lethal GVHD and improve survival of mice from radiation injury. We show these effects could be mediated in part through suppression of human T cell proliferation and may have attenuated host tissue injury in part by enhancing murine fibroblast proliferation. MEMs are a unique MØ subset with therapeutic potential for the management of GVHD and/or protection from radiation-induced injury.


Assuntos
Comunicação Celular/imunologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Doença Enxerto-Hospedeiro/terapia , Macrófagos/imunologia , Células-Tronco Mesenquimais/imunologia , Lesões por Radiação/terapia , Animais , Humanos , Inflamação/imunologia , Interleucina-6/biossíntese , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Células-Tronco Mesenquimais/citologia , Camundongos
7.
J Clin Oncol ; 35(9): 955-962, 2017 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-28297626

RESUMO

In this review, we examine the genomic landscapes of lymphomas that arise from B, T, and natural killer cells. Lymphomas represent a striking spectrum of clinical behaviors. Although some lymphomas are curable with standard therapy, the majority of the affected patients succumb to their disease. Here, the genetic underpinnings of these heterogeneous entities are reviewed. We consider B-cell lymphomas, including Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, and primary mediastinal B-cell lymphoma. We also examine T-cell lymphomas, including anaplastic large-cell lymphoma, angioimmunoblastic T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma, and other peripheral T-cell lymphomas. Together, these malignancies make up most lymphomas diagnosed around the world. Genomic technologies, including microarrays and next-generation sequencing, have enabled a better understanding of the molecular underpinnings of these cancers. We describe the broad genomics findings that characterize these lymphoma types and discuss new therapeutic opportunities that arise from these findings.


Assuntos
Linfoma não Hodgkin/genética , Linfoma não Hodgkin/terapia , Genômica/métodos , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/metabolismo , Terapia de Alvo Molecular , Mutação , Transdução de Sinais/genética
8.
Cancer Discov ; 7(4): 369-379, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28122867

RESUMO

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.


Assuntos
DNA Helicases/genética , Histona-Lisina N-Metiltransferase/genética , Neoplasias Hepáticas/genética , Linfoma de Células T/genética , Neoplasias Esplênicas/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , Pré-Escolar , Proteínas de Ligação a DNA , Proteína Potenciadora do Homólogo 2 de Zeste , Exoma/genética , Feminino , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Esplênicas/complicações , Neoplasias Esplênicas/patologia , Fatores de Transcrição , Proteínas Supressoras de Tumor/genética , Adulto Jovem
9.
Blood ; 127(22): 2723-31, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-26989201

RESUMO

GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.


Assuntos
Linfócitos B/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Centro Germinativo/metabolismo , Linfoma de Células B/metabolismo , Animais , Linfócitos B/patologia , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Centro Germinativo/patologia , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/metabolismo , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética
10.
Blood ; 123(19): 2988-96, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24682267

RESUMO

In this study, we define the genetic landscape of mantle cell lymphoma (MCL) through exome sequencing of 56 cases of MCL. We identified recurrent mutations in ATM, CCND1, MLL2, and TP53. We further identified a number of novel genes recurrently mutated in patients with MCL including RB1, WHSC1, POT1, and SMARCA4. We noted that MCLs have a distinct mutational profile compared with lymphomas from other B-cell stages. The ENCODE project has defined the chromatin structure of many cell types. However, a similar characterization of primary human mature B cells has been lacking. We defined, for the first time, the chromatin structure of primary human naïve, germinal center, and memory B cells through chromatin immunoprecipitation and sequencing for H3K4me1, H3K4me3, H3Ac, H3K36me3, H3K27me3, and PolII. We found that somatic mutations that occur more frequently in either MCLs or Burkitt lymphomas were associated with open chromatin in their respective B cells of origin, naïve B cells, and germinal center B cells. Our work thus elucidates the landscape of gene-coding mutations in MCL and the critical interplay between epigenetic alterations associated with B-cell differentiation and the acquisition of somatic mutations in cancer.


Assuntos
Linfócitos B/metabolismo , Cromatina/genética , Genômica , Linfoma de Célula do Manto/genética , Mutação , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Cromatina/metabolismo , Ciclina D1/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Exoma/genética , Redes Reguladoras de Genes , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Histonas/metabolismo , Humanos , Linfoma de Célula do Manto/patologia , Metilação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Proteína do Retinoblastoma/genética , Análise de Sequência de DNA , Proteínas de Ligação a Telômeros/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética
11.
Nat Genet ; 44(12): 1321-5, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23143597

RESUMO

Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.


Assuntos
Linfoma de Burkitt/genética , Mutação , Amônia-Liases/genética , Sequência de Bases , Linhagem Celular Tumoral , Chaperonina com TCP-1/genética , DNA Helicases/genética , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Genes myc/genética , Genoma Humano , Glutamato Formimidoiltransferase/genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas Inibidoras de Diferenciação/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas de Membrana/genética , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-ret/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética , Translocação Genética
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