RESUMEN
A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2 translocation status, lymphoma-associated chromosomal gains/losses, and assessment of mutations in 220 lymphoma-associated genes by massively parallel sequencing. All cases showed a diffuse growth pattern around well- to ill-defined residual germinal centers, uniform CD23 expression, mixed centrocytic/centroblastic cytology, and expression of at least one germinal center marker. Ten of 11 involved inguinal lymph nodes, 5 solely. By fluorescence in situ hybridization analysis, the vast majority lacked IGH/BCL2 translocation (9/11). Deletion of 1p36 was observed in five cases and included TNFRSF14. Of the six cases lacking 1p36 deletion, TNFRSF14 mutations were identified in three, highlighting the strong association of 1p36/TNFRSF14 abnormalities with this follicular lymphoma variant. In addition, 9 of the 11 cases tested (82%) had STAT6 mutations and nuclear P-STAT6 expression was detectable in the mutated cases by immunohistochemistry. The proportion of STAT6 mutations is higher than recently reported in conventional follicular lymphoma (11%). These findings lend support for a clinicopathologic variant of t(14;18) negative nodal follicular lymphoma and suggests importance of the interleukin (IL)-4/JAK/STAT6 pathway in this variant.
Asunto(s)
Biomarcadores de Tumor/genética , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Linfoma Folicular/genética , Mutación , Receptores de IgE/análisis , Miembro 14 de Receptores del Factor de Necrosis Tumoral/genética , Factor de Transcripción STAT6/genética , Translocación Genética , Adulto , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Deleción Cromosómica , Trastornos de los Cromosomas/inmunología , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 1/inmunología , Análisis Mutacional de ADN/métodos , Femenino , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma Folicular/química , Linfoma Folicular/inmunología , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Fenotipo , Fosforilación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Factor de Transcripción STAT6/análisisRESUMEN
Translation is often repressed in cell lines that are exposed to hypoxic conditions (0.5% - 1.5% O2) but this repression requires prolonged exposure (> 16 h). We report here that prolonged exposure to hypoxia results in the depletion of glucose from the media and that the loss of glucose correlates with the shut down in translation. Furthermore, we show that the addition of glucose or reoxygenation restores translation in hypoxic PC3 cells. This indicates that both glucose depletion and hypoxia are required for translational repression. We also show that eIF2alpha phosphorylation is reversed by glucose addition. Moreover, we present data that strongly indicate that eIF2alpha phosphorylation as well as the translational inhibition that occurs when cells are grown under conditions of glucose depletion and hypoxia is pancreatic eIF2alpha kinase (PERK) independent. We believe this is the first report to show that glucose depletion is required for translational repression under hypoxic conditions and that this explains why prolonged exposure to hypoxia is required for this inhibition. Since the physiological conditions that lead to tumor hypoxia would also likely lead to reduced glucose levels, understanding the interplay of glucose and hypoxia in regulating tumor metabolism will provide important information on the growth and development of solid tumors.
Asunto(s)
Hipoxia de la Célula/genética , Hipoxia de la Célula/fisiología , Glucosa/metabolismo , Biosíntesis de Proteínas , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Medios de Cultivo Condicionados , Factor 2 Eucariótico de Iniciación/metabolismo , Glucosa/farmacología , Glutamina/metabolismo , Humanos , Cinética , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos , Fosforilación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , ARN Interferente Pequeño/genética , Serina-Treonina Quinasas TOR , Factores de Transcripción/metabolismo , eIF-2 Quinasa/antagonistas & inhibidores , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
Genomic copy number alterations (CNAs) in diffuse large B-cell lymphoma (DLBCL) have roles in disease pathogenesis, but overall clinical relevance remains unclear. Herein, an unbiased algorithm was uniformly applied across three genome profiling datasets comprising 392 newly-diagnosed DLBCL specimens that defined 32 overlapping CNAs, involving 36 minimal common regions (MCRs). Scoring criteria were established for 50 aberrations within the MCRs while considering peak gains/losses. Application of these criteria to independent datasets revealed novel candidate genes with coordinated expression, such as CNOT2, potentially with pathogenic roles. No one single aberration significantly associated with patient outcome across datasets, but genomic complexity, defined by imbalance in more than one MCR, significantly portended adverse outcome in two of three independent datasets. Thus, the standardized scoring of CNAs currently developed can be uniformly applied across platforms, affording robust validation of genomic imbalance and complexity in DLBCL and overall clinical utility as biomarkers of patient outcome.