RESUMEN
Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. Eosinophil, B-cell, and mast cell signatures were enriched in children, whereas macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs 90.3%; log-rank P = .0138) independent of interim response, stage, fever, and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT00025259.
Asunto(s)
Perfilación de la Expresión Génica , Enfermedad de Hodgkin/genética , Niño , Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/diagnóstico , Humanos , Modelos Biológicos , Pronóstico , Supervivencia sin Progresión , Microambiente TumoralRESUMEN
Despite continuing improvements in the management of classical Hodgkin lymphoma (cHL), relapse remains associated with a risk of lymphoma-related mortality. The biological composition of relapse tumour biopsies shows interpatient variability, which can be leveraged to design prognostic biomarkers. Here, we validated the RHL30 assay, a previously reported gene expression model in an independent cohort of 41 patients with relapsed cHL. Patients classified as high-risk by the RHL30 assay had inferior failure-free survival (FFS) after autologous stem cell transplantation (2-year FFS 41% vs. 92%, P = 0·035). The RHL30 model is a robust biomarker that risk-stratifies patients considered for autologous stem cell transplantation.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Adulto , Autoinjertos , Femenino , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/terapia , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
We recently found that FOXO1 repression contributes to the oncogenic program of classical Hodgkin lymphoma (cHL). Interestingly, FOXO3A, another member of the FOXO family, was reported to be expressed in the malignant Hodgkin and Reed-Sternberg cells of cHL at higher levels than in non-Hodgkin lymphoma subtypes. We thus aimed to investigate mechanisms responsible for the maintenance of FOXO3A as well as the potential role of FOXO3A in cHL. Here, we show that high FOXO3A levels in cHL reflect a B-cell-differentiation-specific pattern. In B cells, FOXO3A expression increases during the process of centroblast to plasma cell (PC) differentiation. FOXO3A levels in cHL were found higher than in germinal center B cells, but lower than in terminally differentiated PCs. This intermediate FOXO3A expression in cHL might manifest the "abortive PC differentiation" phenotype. This assumption was further corroborated by the finding that overexpression of FOXO3A in cHL cell lines induced activation of the master PC transcription factor PRDM1α. As factors attenuating FOXO3A expression in cHL, we identified MIR155 and constitutive activation of extracellular signal-regulated kinase. Finally, we demonstrate the importance of FOXO3A expression in cHL using an RNA interference approach. We conclude that tightly regulated expression of FOXO3A contributes to the oncogenic program and to the specific phenotype of cHL.
Asunto(s)
Diferenciación Celular , Proteína Forkhead Box O3/biosíntesis , Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/metabolismo , Proteínas de Neoplasias/biosíntesis , Células Plasmáticas/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Proteína Forkhead Box O3/genética , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas de Neoplasias/genética , Células Plasmáticas/patología , ARN Neoplásico/genética , ARN Neoplásico/metabolismoRESUMEN
Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic IL4R mutations in 15 of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8, leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain of function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish IL4R mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.
Asunto(s)
Subunidad alfa del Receptor de Interleucina-4/genética , Quinasas Janus/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/metabolismo , Mutación , Factores de Transcripción STAT/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Ratones , Fosforilación , Transducción de SeñalRESUMEN
The clinical significance of MYC and BCL2 genetic alterations in diffuse large B-cell lymphoma (DLBCL), apart from translocations, has not been comprehensively investigated using high-resolution genetic assays. In this study, we profiled MYC and BCL2 genetic alterations using next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL cases treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) at the British Columbia Cancer Agency. Cell-of-origin (COO) subtype was determined by Lymph2Cx digital gene expression profiling. We showed that the incidence of MYC/BCL2 genetic alterations and their clinical significance were largely dependent on COO subtypes. It is noteworthy that the presence of BCL2 gain/amplification is significantly associated with poor outcome in activated B-cell-like and BCL2 translocation with poor outcome in germinal center B-cell subtypes, respectively. Both have prognostic significance independent of MYC/BCL2 dual expression and the International Prognostic Index (IPI). Furthermore, the combination of BCL2 genetic alterations with IPI identifies markedly worse prognostic groups within individual COO subtypes. Thus, high-resolution genomic assays identify extremely poor prognostic groups within each COO subtype on the basis of BCL2 genetic status in this large, uniformly R-CHOP-treated population-based cohort of DLBCL. These results suggest COO subtype-specific biomarkers based on BCL2 genetic alterations can be used to risk-stratify patients with DLBCL treated with immunochemotherapy.
Asunto(s)
Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Variaciones en el Número de Copia de ADN/genética , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación/genética , Fenotipo , Pronóstico , Factores de Tiempo , Resultado del TratamientoRESUMEN
High-throughput sequencing has significantly contributed to revealing the molecular underpinnings of B-cell lymphomagenesis and disease progression. It is now a widely accepted concept that the diversity of clinical responses to front-line therapy and the development of relapsed/refractory disease are in part explained by 'inter-patient' genetic heterogeneity measurable by individual sets of somatic gene alterations in tumor genomes. Moreover, extensive 'intra-tumor' heterogeneity on the genotypic and phenotypic levels is the product of ongoing tumor evolution and adaptation to various selective pressures during cancer initiation, progression, and therapeutic intervention. As the management of disease progression remains one of the most significant clinical challenges, it is becoming increasingly important to delineate how B-cell lymphomas evolve over time and to develop progression-related biomarker assays. Toward this goal, recent investigations have moved from studying lymphoma biology at initial diagnosis to doing so at multiple time points during the disease course. Profiling progressed tumors, and in particular paired biopsies at initial diagnosis and disease progression of the same patients, has led to novel insights into clonal tumor evolution and tumor microenvironment dynamics. This review discusses the latest findings on genomic alterations and microenvironment biology associated with relapsed/refractory B-cell lymphomas, with a particular emphasis on alterations that are acquired or become more prevalent at disease progression. We also describe overarching tumor evolution patterns, and highlight emerging precision medicine methodologies that can aid in an improved understanding and management of relapsed/refractory disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Biomarcadores de Tumor/genética , Genómica/métodos , Linfoma de Células B/genética , Linfoma de Células B/patología , Patología Molecular/métodos , Evolución Clonal , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Microambiente TumoralRESUMEN
Non-Hodgkin lymphomas (NHLs) are the most common cancer to affect pet dogs. In contrast to the many genes whose mutation contributes to lymphomagenesis in humans, relatively little is known about the acquired genetic alterations that lead to canine B-cell lymphomas (cBCLs). We performed a survey of 84 canine NHL tumors to identify genes affected by somatic point mutations. We found mutations affecting TRAF3, which encodes a negative regulator of nuclear factor (NF)-κB, to be a common feature of cBCLs, with mutations observed in 44% of tumors including a combination of somatic and rare germ-line variants. Overall, 30% of the tumors contained ≥1 somatic TRAF3 mutation. The majority of mutations are predicted to cause loss of TRAF3 protein including those impacting reading frame and splicing. To determine whether TRAF3 loss might be relevant to human NHL, we also analyzed 148 human diffuse large B-cell lymphoma (DLBCL) tumors and identified loss of TRAF3 as a common event, affecting â¼9% of DLBCLs, and reduced expression of TRAF3 among deleted cases. This study implicates mutations affecting NF-κB activity as a novel genetic commonality between human and canine NHLs and supports the potential utility of cBCLs with mutated TRAF3 as a model of the more aggressive activated B-cell subgroup of DLBCL.
Asunto(s)
Linfoma de Células B/genética , Linfoma de Células B Grandes Difuso/genética , Mutación , Factor 3 Asociado a Receptor de TNF/genética , Animales , Linfocitos B/metabolismo , Perros , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , FN-kappa B/metabolismo , Factor 3 Asociado a Receptor de TNF/metabolismoRESUMEN
Effective treatment of diffuse large B-cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in a DLBCL cohort treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA sequencing data revealed novel deletions in RCOR1 to be associated with unfavorable progression-free survival (P = .001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (P = .023). The prognostic significance of the 233-gene signature for overall survival was reproduced in an independent cohort comprising 195 R-CHOP-treated patients (P = .039). Additionally, we discovered that within the International Prognostic Index low-risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. We present a novel and reproducible molecular subgroup of DLBCL that impacts risk-stratification of R-CHOP-treated DLBCL patients and reveals a possible new avenue for therapeutic intervention strategies.
Asunto(s)
Proteínas Co-Represoras/genética , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Proteínas del Tejido Nervioso/genética , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Femenino , Eliminación de Gen , Técnicas de Silenciamiento del Gen , Humanos , Factores Inmunológicos/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Pronóstico , Rituximab , Transcriptoma , Vincristina/uso terapéuticoRESUMEN
Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL.
Asunto(s)
Linfocitos B/patología , Transformación Celular Neoplásica/patología , Linfoma Folicular/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Linfocitos B/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Antígenos CD79/genética , Transformación Celular Neoplásica/genética , Femenino , Centro Germinal/metabolismo , Centro Germinal/patología , Guanilato Ciclasa/genética , Humanos , Linfoma Folicular/genética , Masculino , Persona de Mediana Edad , Mutación , Factor 88 de Diferenciación Mieloide/genéticaRESUMEN
BACKGROUND: Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. METHODS AND FINDINGS: Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. CONCLUSIONS: Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
Asunto(s)
Evolución Clonal , Progresión de la Enfermedad , Linfoma Folicular/fisiopatología , Células Clonales , Humanos , Linfoma Folicular/genética , MutaciónRESUMEN
The pathogenesis of primary mediastinal large B-cell lymphoma (PMBCL) is incompletely understood. Recently, specific genotypic and phenotypic features have been linked to tumor cell immune escape mechanisms in PMBCL. We studied 571 B-cell lymphomas with a focus on PMBCL. Using fluorescence in situ hybridization here, we report that the programmed death ligand (PDL) locus (9p24.1) is frequently and specifically rearranged in PMBCL (20%) as compared with diffuse large B-cell lymphoma, follicular lymphoma, and Hodgkin lymphoma. Rearrangement was significantly correlated with overexpression of PDL transcripts. Utilizing high-throughput sequencing techniques, we characterized novel translocations and chimeric fusion transcripts involving PDLs at base-pair resolution. Our data suggest that recurrent genomic rearrangement events underlie an immune privilege phenotype in a subset of B-cell lymphomas.
Asunto(s)
Antígeno B7-H1/genética , Linfoma de Células B Grandes Difuso/genética , Neoplasias del Mediastino/genética , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Translocación Genética , Línea Celular Tumoral , Cromosomas Humanos Par 9 , Variaciones en el Número de Copia de ADN , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/epidemiología , Neoplasias del Mediastino/epidemiología , MutaciónRESUMEN
The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-κB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation. Here we show that FOXO1 directly upregulates the full-length isoform PRDM1α in cHL cell lines. We also observed a positive correlation between FOXO1 and PRDM1 expression levels in primary Hodgkin-Reed-Sternberg cells. Further, we show that PRDM1α acts as a tumor suppressor in cHL at least partially by blocking MYC. Here we provide a link between FOXO1 repression and PRDM1α downregulation in cHL and identify PRDM1α as a tumor suppressor in cHL. The data support a potential role for FOXO transcription factors in normal PC differentiation.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Células Plasmáticas/patología , Proteínas Represoras/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Regulación hacia Abajo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Enfermedad de Hodgkin/metabolismo , Humanos , Células Plasmáticas/citología , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-myc/metabolismo , Células de Reed-Sternberg/metabolismo , Células de Reed-Sternberg/patología , Proteínas Represoras/genética , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
Primary testicular diffuse large B cell lymphoma (PTL) is an aggressive malignancy that occurs in the immune-privileged anatomical site of the testis. We have previously shown that structural genomic rearrangements involving the MHC class II transactivator CIITA and programmed death ligands (PDLs) 1 and 2 are frequent across multiple B cell lymphoma entities. Specifically in PTL, we found rearrangements in the PDL locus by fluorescence in situ hybridization (FISH). However, breakpoint anatomy and rearrangement partners were undetermined, while CIITA rearrangements had not been reported previously in PTL. Here, we performed bacterial artificial chromosome capture sequencing on three archival, formalin-fixed, paraffin-embedded tissue biopsies, interrogating 20 known rearrangement hotspots in B cell lymphomas. We report novel CIITA, FOXP1 and PDL rearrangements involving IGHG4, FLJ45248, RFX3, SMARCA2 and SNX29. Moreover, we present immunohistochemistry data supporting the association between PDL rearrangements and increased protein expression. Finally, using FISH, we show that CIITA (8/82; 10%) and FOXP1 (5/74; 7%) rearrangements are recurrent in PTL. In summary, we describe rearrangement frequencies and novel rearrangement partners of the CIITA, FOXP1 and PDL loci at base-pair resolution in a rare, aggressive lymphoma. Our data suggest immune-checkpoint inhibitor therapy as a promising intervention for PTL patients harbouring PDL rearrangements.
Asunto(s)
Antígeno B7-H1/genética , Factores de Transcripción Forkhead/genética , Reordenamiento Génico de Linfocito B/genética , Linfoma de Células B Grandes Difuso/genética , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Proteínas Represoras/genética , Neoplasias Testiculares/genética , Puntos de Rotura del Cromosoma , Cromosomas Artificiales Bacterianos , Eliminación de Gen , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Proteínas Nucleares/genética , Recurrencia , Transactivadores/genética , Translocación Genética/genéticaRESUMEN
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte rich large B cell lymphoma (THRLBCL) usually affect middle-aged men, show tumour cells with a B cell phenotype and a low tumour cell content. Whereas the clinical behaviour of NLPHL is indolent, THRLBCL presents with advanced stage disease and an aggressive behaviour. In the present study, array comparative genomic hybridization was performed in seven typical NLPHL, four THRLBCL-like NLPHL variants, six THRLBCL and four diffuse large B cell lymphomas (DLBCL) derived from NLPHL. The number of genomic aberrations was higher in THRLBCL compared with typical and THRLBCL-like variant of NLPHL. Gains of 2p16.1 and losses of 2p11.2 and 9p11.2 were commonly observed in typical and THRLBCL-like variants of NLPHL as well as THRLBCL. Gains of 2p16.1, affecting the REL locus were confirmed in an independent cohort. Expression of the REL protein was observed at similar frequencies in typical and THRLBCL-like variant of NLPHL as well as THRLBCL (33-38%). In conclusion, the present study reveals further similarities between NLPHL and THRLBCL on the genomic level, confirming that these entities are part of a pathobiological spectrum with common molecular features, but varying clinical presentations.
Asunto(s)
Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Aberraciones Cromosómicas , Mapeo Cromosómico , Hibridación Genómica Comparativa , Histiocitos/metabolismo , Histiocitos/patología , Enfermedad de Hodgkin/metabolismo , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/metabolismo , Proteínas Proto-Oncogénicas c-rel/genética , Proteínas Proto-Oncogénicas c-rel/metabolismo , Reproducibilidad de los Resultados , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer composed of at least 2 molecular subtypes that differ in gene expression and distribution of mutations. Recently, application of genome/exome sequencing and RNA-seq to DLBCL has revealed numerous genes that are recurrent targets of somatic point mutation in this disease. Here we provide a whole-genome-sequencing-based perspective of DLBCL mutational complexity by characterizing 40 de novo DLBCL cases and 13 DLBCL cell lines and combining these data with DNA copy number analysis and RNA-seq from an extended cohort of 96 cases. Our analysis identified widespread genomic rearrangements including evidence for chromothripsis as well as the presence of known and novel fusion transcripts. We uncovered new gene targets of recurrent somatic point mutations and genes that are targeted by focal somatic deletions in this disease. We highlight the recurrence of germinal center B-cell-restricted mutations affecting genes that encode the S1P receptor and 2 small GTPases (GNA13 and GNAI2) that together converge on regulation of B-cell homing. We further analyzed our data to approximate the relative temporal order in which some recurrent mutations were acquired and demonstrate that ongoing acquisition of mutations and intratumoral clonal heterogeneity are common features of DLBCL. This study further improves our understanding of the processes and pathways involved in lymphomagenesis, and some of the pathways mutated here may indicate new avenues for therapeutic intervention.
Asunto(s)
Biomarcadores de Tumor/química , Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN/genética , Genoma Humano , Linfoma de Células B Grandes Difuso/genética , Mutación/genética , Subunidades alfa de la Proteína de Unión al GTP G12-G13/química , Subunidades alfa de la Proteína de Unión al GTP G12-G13/genética , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
In classical Hodgkin lymphoma (CHL), 20%-30% of patients experience relapse or progressive disease after initial treatment. The pathogenesis and biology of treatment failure are still poorly understood, in part because the molecular phenotype of the rare malignant Hodgkin Reed-Sternberg (HRS) cells is difficult to study. Here we examined microdissected HRS cells from 29 CHL patients and 5 CHL-derived cell lines by gene expression profiling. We found significant overlap of HL-specific gene expression in primary HRS cells and HL cell lines, but also differences, including surface receptor signaling pathways. Using integrative analysis tools, we identified target genes with expression levels that significantly correlated with genomic copy-number changes in primary HRS cells. Furthermore, we found a macrophage-like signature in HRS cells that significantly correlated with treatment failure. CSF1R is a representative of this signature, and its expression was significantly associated with progression-free and overall survival in an independent set of 132 patients assessed by mRNA in situ hybridization. A combined score of CSF1R in situ hybridization and CD68 immunohistochemistry was an independent predictor for progression-free survival in multivariate analysis. In summary, our data reveal novel insights into the pathobiology of treatment failure and suggest CSF1R as a drug target of at-risk CHL.
Asunto(s)
Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Enfermedad de Hodgkin/genética , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Células de Reed-Sternberg/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Femenino , Dosificación de Gen , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Humanos , Hibridación in Situ , Captura por Microdisección con Láser , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , ARN Mensajero/biosíntesis , Recurrencia , Células de Reed-Sternberg/efectos de los fármacos , Células de Reed-Sternberg/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Recently, the landscape of single base mutations in diffuse large B-cell lymphoma (DLBCL) was described. Here we report the discovery of a gene fusion between TBL1XR1 and TP63, the only recurrent somatic novel gene fusion identified in our analysis of transcriptome data from 96 DLBCL cases. Based on this cohort and a further 157 DLBCL cases analyzed by FISH, the incidence in de novo germinal center B cell-like (GCB) DLBCL is 5% (6 of 115). The fusion appears exclusive to GCB and was not seen in 138 non-GCB cases examined (P = .008, Fisher exact test) but was present at low incidence in follicular lymphoma (1 of 81). In all 7 cases identified, the 3' end of the fusion consists of exons 4 and onwards of TP63. The recurrence, subtype enrichment, and the remarkably conserved nature of the TP63 portion of the fusion suggest an important functional role in the lymphomas that harbor this event.
Asunto(s)
Linfoma de Células B/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Secuencia de Bases , Cromosomas Humanos Par 3/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Hibridación Fluorescente in Situ , Incidencia , Linfoma de Células B/epidemiología , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Datos de Secuencia MolecularRESUMEN
Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a growing prevalence of sleep problems associated with significant behavioral problems and more severe autism clinical presentation. Little is known about the relationships between autism traits and sleep problems in Hong Kong. Therefore, this study aimed to examine whether children with autism have increased sleep problems than non-autistic children in Hong Kong. The secondary objective was to examine the factors associated with sleep problems in an autism clinical sample. Methods: This cross-sectional study recruited 135 children with autism and 102 with the same age range of non-autistic children, aged between 6 and 12 years. Both groups were screened and compared on their sleep behaviors using the Children's Sleep Habits Questionnaire (CSHQ). Results: Children with autism had significantly more sleep problems than non-autistic children [t (226.73) = 6.20, p < 0.001]. Bed -sharing [beta = 0.25, t (165) = 2.75, p = 0.07] and maternal age at birth [beta = 0.15, t (165) = 2.05, p = 0.043] were significant factors associated with CSHQ score on the top of autism traits. Stepwise linear regression modeling identified that only separation anxiety disorder (beta = 4.83, t = 2.40, p = 0.019) best-predicted CSHQ. Conclusion: In summary, autistic children suffered from significantly more sleep problems and co-occurring separation anxiety disorder brings greater sleep problems as compared to non-autistic children. Clinicians should be more aware of sleep problems to provide more effective treatments to children with autism.
RESUMEN
Emerging evidence indicates a major impact for the tumor microenvironment (TME) and immune escape in the pathogenesis and clinical course of classical Hodgkin lymphoma (cHL). We used gene expression profiling (n = 88), CIBERSORT, and multiplex immunohistochemistry (n = 131) to characterize the immunoprofile of cHL TME and correlated the findings with survival. Gene expression analysis divided tumors into subgroups with T cell-inflamed and -noninflamed TME. Several macrophage-related genes were upregulated in samples with the non-T cell-inflamed TME, and based on the immune cell proportions, the samples clustered according to the content of T cells and macrophages. A cluster with high proportions of checkpoint protein (programmed cell death protein 1, PD-1 ligands, indoleamine 2,3 dioxygenase 1, lymphocyte-activation gene 3, and T-cell immunoglobulin and mucin domain containing protein 3) positive immune cells translated to unfavorable overall survival (OS) (5-year OS 76% vs 96%; P = .010) and remained an independent prognostic factor for OS in multivariable analysis (HR, 4.34; 95% CI, 1.05-17.91; P = .043). cHL samples with high proportions of checkpoint proteins overexpressed genes coding for cytolytic factors, proposing paradoxically that they were immunologically active. This checkpoint molecule gene signature translated to inferior survival in a validation cohort of 290 diagnostic cHL samples (P < .001) and in an expansion cohort of 84 cHL relapse samples (P = .048). Our findings demonstrate the impact of T cell- and macrophage-mediated checkpoint system on the survival of patients with cHL.