RESUMEN
DC is caused by defects at the level of telomere maintenance, and cells from patients with this disease have abnormally short telomeres and show premature senescence. One consequence of DC is bone marrow failure. Thus, patients with DC often require HSCT. However, HSCT does not ameliorate other DC-related manifestations. In fact, HSCT can accelerate organ dysfunction due to treatment-related complications, and solid organ transplantation is required in some patients with DC. In this report, we describe the clinical course of a 5-year-old boy who was transferred to our hospital because of progressive dyspnea, 2 years after HSCT. At admission, he had tachypnea and hypoxemia. A liver biopsy was performed for suspected HPS caused by PH, and LT was considered. Eventually, his hypoxemia worsened, and he was transferred to a PICU and started on VA ECMO. He subsequently underwent a CLLT. ECMO was stopped on post-operative day 12, extubation was achieved on post-operative day 29, and the patient recovered well from the surgery. Our results show that CLLT could be a life-saving treatment option for DC patients with very severe HPS in whom a poor outcome is expected after LT.
Asunto(s)
Disqueratosis Congénita/complicaciones , Síndrome Hepatopulmonar/cirugía , Hipertensión Portal/cirugía , Trasplante de Hígado/métodos , Trasplante de Pulmón/métodos , Preescolar , Síndrome Hepatopulmonar/etiología , Humanos , Hipertensión Portal/etiología , Masculino , Gravedad del PacienteRESUMEN
Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.
Asunto(s)
Reordenamiento Génico , Linfoma de Células B de la Zona Marginal/genética , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas/genética , Neoplasias Gástricas/genética , Factor 3 Asociado a Receptor de TNF/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Adulto , Proteína 10 de la LLC-Linfoma de Células B/genética , Femenino , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Mutación , FN-kappa B/genética , Estadificación de Neoplasias , Estudios Retrospectivos , Transducción de Señal/genética , Neoplasias Gástricas/patologíaRESUMEN
Spleen tyrosine kinase (SYK) has predominantly been studied in hematopoietic cells, where it is involved in immunoreceptor-mediated signaling. However, SYK expression has been shown in numerous non-hematopoietic cells, and its downregulation has been shown to be involved in tumor formation and progression. SYK methylation has been demonstrated to identify a subset of hepatocellular carcinoma (HCC) cases with poor prognosis, but little is known regarding the biological role of SYK in HCC. We found that SYK methylation is a common event in HCC, and is inversely associated with its expression. We established stable HCC cell lines with inducible SYK expression vectors, and compared the differential RNA expression profiles of HCC cell lines with or without the induction of SYK. Gene ontology analysis revealed that the SYK-regulated genes were enriched for genes involved in cell adhesion. Accordingly, we found that the induction of SYK expression increased the adhesion of cells to fibronectin and decreased cell migration and invasion, and that cessation of SYK overexpression increased cell migration and invasion. Our findings suggest that SYK is involved in regulating cell to matrix adhesions, and that SYK loss affects the migration, and invasion of HCC cells.
Asunto(s)
Carcinoma Hepatocelular/etiología , Islas de CpG , Metilación de ADN , Neoplasias Hepáticas/etiología , Regiones Promotoras Genéticas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adulto , Anciano , Carcinogénesis , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/mortalidad , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Humanos , Integrina beta1/fisiología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/fisiología , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/fisiología , Bazo/enzimología , Quinasa SykRESUMEN
Dual-specificity phosphatase 5 (DUSP5), which regulates the duration and magnitude of ERK1/2 phosphoactivation within the mitogen-activated protein kinase (MAPK) cascade, has recently been proposed to be a tumor suppressor. However, the epigenetic regulation of DUSP5 and its critical roles in gastric cancer (GC) remain unknown. We compared differential RNA expression profiles of GC cell lines with or without treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine. DUSP5 expression was dramatically decreased by DNA methylation. Hypermethylation of the DUSP5 promoter was detected in GC tissue samples, but not in normal healthy gastric mucosa samples. Restoring DUSP5 expression in DUSP5-silenced GC cell lines decreased their growth and colony-forming ability by causing arrest in the transition from G1 to S phase in the cell cycle as a result of dephosphorylation of ERK1/2 in the nucleus. Moreover, in a set of surgically resected GC cases (n = 179), GCs with DUSP5 promoter region hypermethylation (30.2%) exhibited significantly shortened survival, compared with GCs without DUSP5 methylation (P = 0.009). These results suggest that silencing of DUSP5 by promoter hypermethylation causes increased maintenance of phosphorylated ERK1/2, driving cell proliferation and contributing to gastric carcinogenesis. Furthermore, DUSP5 methylation may serve as a prognostic marker for GC, but this requires validation in a larger set of GC samples.
Asunto(s)
Transformación Celular Neoplásica/genética , Islas de CpG/genética , Metilación de ADN/genética , Regulación hacia Abajo/genética , Fosfatasas de Especificidad Dual/genética , Regiones Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Azacitidina/farmacología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Núcleo Celular/efectos de los fármacos , Núcleo Celular/enzimología , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/patología , Regulación hacia Abajo/efectos de los fármacos , Fosfatasas de Especificidad Dual/metabolismo , Epigénesis Genética/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fosforilación/efectos de los fármacos , Pronóstico , Reproducibilidad de los Resultados , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/patologíaRESUMEN
Focal CpG island hypermethylation and diffuse genomic hypomethylation signify the changes in the DNA methylation status in cancer cells. ALU and LINE-1 repetitive DNA elements comprise ~28% of the human genome. PCR-based measurements of these repetitive DNA elements can be used as a surrogate marker of the genomewide methylation content. Our study aimed to identify the timing of ALU and LINE-1 hypomethylations during multistep gastric carcinogenesis and their prognostic implications in gastric cancer (GC). In our study, we analyzed the methylation statuses of ALU and LINE-1 in 249 cases of gastric biopsy samples and another independent set of 198 cases of advanced GC by pyrosequencing. Regardless of the Helicobacter pylori infection status, a significant decrease in the ALU methylation levels was noted during the transitions from chronic gastritis to intestinal metaplasia and from gastric adenoma to GC. LINE-1 methylation decreased during the transition from intestinal metaplasia to gastric adenoma and no further decrease occurred during the transition from gastric adenoma to GC. A low LINE-1 methylation status was strongly associated with poor prognosis in GC. A multivariate analysis revealed that LINE-1 methylation status was an independent prognostic factor. Our findings suggest that ALU and LINE-1 hypomethylations are early events during multistep gastric carcinogenesis. Furthermore, the LINE-1 methylation status can be used as a molecular biomarker to define a subset of GC patients with poor prognosis.
Asunto(s)
Elementos Alu/genética , Metilación de ADN , Elementos de Nucleótido Esparcido Largo/genética , Neoplasias Gástricas/genética , Anciano , Islas de CpG , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Gástricas/etiología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patologíaRESUMEN
PURPOSE: This study aims to determine the relationship between CpG island DNA hypermethylation and global genomic DNA hypomethylation and their prognostic implications in hepatocellular carcinoma. The association of DNA methylation changes with clinicopathologic factors and the chronological ordering of DNA methylation changes along multistep hepatocarcinogenesis were also assessed. EXPERIMENTAL DESIGN: Hepatocellular carcinoma (n = 20) and nonneoplastic liver samples (n = 72) were analyzed for their methylation status at 41 CpG island loci and 3 repetitive DNA elements (LINE-1, ALU, and SAT2) using MethyLight or combined bisulfite restriction analysis. After selection of 19 CpG island loci showing cancer-specific DNA methylation, another set of 99 hepatocellular carcinoma samples was analyzed for these loci. RESULTS: The number of methylated genes in hepatocellular carcinoma was significantly higher in hepatocellular carcinoma patients with a cirrhotic liver than in hepatocellular carcinoma patients with a noncirrhotic liver (9.9 versus 7.0, P = 0.001). Hepatocellular carcinoma from female patients showed a higher number of methylated genes than hepatocellular carcinoma from male patients (11.2 versus 8.4, P = 0.006). The genes CRABP1 and SYK showed significant association between CpG island hypermethylation and patients' poor survival. SAT2 hypomethylation occurred earlier than LINE-1 or ALU hypomethylation along the multistep hepatocarcinogenesis. Depending on the type of CpG island locus, a direct, inverse, or no relationship between CpG island hypermethylation and repetitive DNA hypomethylation was observed in hepatocellular carcinomas. CONCLUSION: The varying relationships between the hypermethylation of individual CpG island loci and the hypomethylation of repetitive elements suggests that they are not mechanically linked. SYK and CRABP1 hypermethylation may serve as useful tumor markers for prognostication of hepatocellular carcinoma patients.
Asunto(s)
Carcinoma Hepatocelular/genética , Islas de CpG , Metilación de ADN , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Femenino , Humanos , Hígado/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND/AIM: Primary hepatic angiosarcoma (PHA) is a rare disease entity with variable morphologic features. Recent findings regarding ROS1 gene rearrangements in PHA may lead to new targeted therapies. PATIENTS AND METHODS: Thirteen cases (4 resected specimens and 9 biopsy samples) underwent histologic review and morphologic patterns were classified according to a previous study as 1) sinusoidal, 2) peliotic, 3) vasoformative, and 4) solid (epithelioid/spindled). ROS1 immunohistochemistry and investigation of the presence of a ROS1 fusion gene by reverse transcription-polymerase chain reaction were performed in available cases. RESULTS: Eight of 13 cases (62%) showed vasoformative patterns. Three cases (23%) were classified as sinusoidal and two (15%) as solid patterns. Mortality rate was 90% (9/10) except for three patients lost in follow up. Only one patient is still alive and has survived for 8 months with the disease. All cases tested did not have ROS1 expression (0/9) or a ROS1 fusion gene (0/4). CONCLUSION: We report 13 cases of PHA with 90% mortality. Vasoformative PHA is the most common histologic type. New findings on ROS1 fusion gene rearrangements could lead to the development of novel targeted therapeutics for PHA patients with dismal prognosis.
Asunto(s)
Reordenamiento Génico , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Hemangiosarcoma/metabolismo , Hemangiosarcoma/mortalidad , Humanos , Inmunohistoquímica , Corea (Geográfico) , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Adulto JovenRESUMEN
The cellular lineage of extranodal NK/T-cell lymphoma, nasal-type (ENKTL), is determined by expression of T-cell receptor (TR) or TR gene rearrangement. In ENKTL, from TR immunohistochemistry, it may often be difficult to decide whether TR-positive cells are tumor cells or not, especially when TR is expressed in a subset of tumor cells. To analyze TR expression pattern and TR rearrangement in T-lineage ENKTL, we performed double immunofluorescence staining for Epstein-Barr virus-encoded small RNAs (EBER)/T-cell receptor (TCR) ßF1 and CD56/TCR ßF1 in 12 cases of ENKTL that showed TCR ßF1 expression in immunohistochemistry. TR gene rearrangement was analyzed using a commercial BIOMED-2 multiplex polymerase chain reaction system. Immunohistochemistry showed that all 12 cases expressed TCR ßF1 in a wide range of infiltrating cells from 100% to <1%. Two of them expressed both TCR ßF1 and TCR cγM1. EBER/TCR-ßF1-positivity was confirmed in 10 cases by double staining. One case failed to show EBER/TCR-ßF1-positive cells but showed a CD56/TCR ßF1-positive result. Among 12 cases, 5 had poor-quality DNA, 3 of them showed no polymerase chain reaction product, and 2 cases showed nonspecific peak of low height. Five of 7 cases with good DNA quality demonstrated monoclonal TR gene rearrangement. Based on TR expression and TR gene rearrangement, 10 of 12 cases of ENKTL were decided as a T-lineage tumor. In conclusion, because of common TR silence and poor DNA quality, consideration of both immunohistochemistry and TR gene rearrangement is necessary to determine the lineage of ENKTL.
Asunto(s)
Genes Codificadores de los Receptores de Linfocitos T/genética , Linfoma Extranodal de Células NK-T/patología , Receptores de Antígenos de Linfocitos T/análisis , Linaje de la Célula , Infecciones por Virus de Epstein-Barr/complicaciones , Reordenamiento Génico , Humanos , Inmunohistoquímica , Linfoma Extranodal de Células NK-T/genética , Linfoma Extranodal de Células NK-T/virología , Reacción en Cadena de la Polimerasa MultiplexRESUMEN
[This corrects the article DOI: 10.18632/oncotarget.14928.].
RESUMEN
Ocular marginal zone lymphoma is a common type of low-grade B-cell lymphoma. To investigate the genomic changes that occur in ocular marginal zone lymphoma, we analyzed 10 cases of ocular marginal zone lymphoma using whole-genome and RNA sequencing and an additional 38 cases using targeted sequencing. Major genetic alterations affecting genes involved in nuclear factor (NF)-κB pathway activation (60%), chromatin modification and transcriptional regulation (44%), and B-cell differentiation (23%) were identified. In whole-genome sequencing, the 6q23.3 region containing TNFAIP3 was deleted in 5 samples (50%). In addition, 5 structural variation breakpoints in the first intron of IL20RA located in the 6q23.3 region was found in 3 samples (30%). In targeted sequencing, a disruptive mutation of TNFAIP3 was the most common alteration (54%), followed by mutations of TBL1XR1 (18%), cAMP response element binding proteins (CREBBP) (17%) and KMT2D (6%). All TBL1XR1 mutations were located within the WD40 domain, and TBL1XR1 mutants transfected into 293T cells increased TBL1XR1 binding with nuclear receptor corepressor (NCoR), leading to increased degradation of NCoR and the activation of NF-κB and JUN target genes. This study confirms genes involving in the activation of the NF-kB signaling pathway is the major driver in the oncogenesis of ocular MZL.
Asunto(s)
Proteína de Unión a CREB/genética , Neoplasias del Ojo/genética , Linfoma de Células B de la Zona Marginal/genética , Mutación , Proteínas Nucleares/genética , Receptores Citoplasmáticos y Nucleares/genética , Proteínas Represoras/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteína de Unión a CREB/metabolismo , Línea Celular Tumoral , Deleción Cromosómica , Cromosomas Humanos Par 6/genética , Neoplasias del Ojo/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Immunoblotting , Linfoma de Células B de la Zona Marginal/metabolismo , Masculino , Microscopía Confocal , Persona de Mediana Edad , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Interferencia de ARN , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Extrahepatic cholangiocarcinoma (EHC) is usually difficult to diagnose by bile cytology because of cellular disintegration. However, DNA samples from bile fluid can provide sufficient materials to screen for the presence of EHC. We developed DNA methylation marker panels that can be used for MethyLight assay-based detection of EHC in bile fluid specimens. The methylation status of 59 DNA methylation markers was investigated in 20 EHC and 20 non-neoplastic gallbladder tissue samples with MethyLight assay to determine cancer-specific DNA methylation markers. Through assaying cancer-specific DNA methylation markers in a training set (n = 40) and validation set (n = 45) of bile fluid specimens from patients with EHC or those without cancer, we selected suitable marker panels that were assessed for their performance in a third set (test set; n = 40). Four marker panels showed a sensitivity of 60% or more and a specificity of 100% in both the training and validation sets, whereas bile cytology displayed a sensitivity of 40% to 46% and a specificity of 100%. In an independent test set of bile fluid samples, a five-gene panel (CCND2, CDH13, GRIN2B, RUNX3, and TWIST1) detected EHC at a sensitivity of 83%, which was far higher than that of bile cytology (46%, P = 0.004). Using bile fluids, a methylation assay consisting of a five-gene panel may be useful for detecting EHC and in helping to increase the sensitivity of preoperative diagnoses.
Asunto(s)
Bilis/citología , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Metilación de ADN , Técnicas de Diagnóstico Molecular/métodos , Biomarcadores de Tumor/genética , Islas de CpG/genética , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Vesícula Biliar/citología , Marcadores Genéticos , Humanos , Adhesión en Parafina , Regiones Promotoras Genéticas , Sensibilidad y Especificidad , Fijación del TejidoRESUMEN
CONTEXT: Helicobacter pylori infection is primarily acquired during childhood and persists throughout life in the absence of eradication with antibiotics. Helicobacter pylori infection induces methylation in the promoter CpG island loci in gastric epithelial cells. Thus, aberrant CpG island hypermethylation in gastric epithelial cells likely occurs early in life, although there are no existing data supporting this notion. OBJECTIVES: To identify whether aberrant CpG island hypermethylation occurs in pediatric stomach mucosa in association with H pylori infection and to compare methylation profiles of samples from pediatric and adult stomach tissues. DESIGN: We analyzed pediatric (n = 47) and adult (n = 38) gastric mucosa samples for their methylation status in 12 promoter CpG island loci using the MethyLight assay and compared the number of methylated genes and the methylation levels in individual genes between H pylori -positive and H pylori -negative sample results and between pediatric and adult samples. RESULTS: The average number of methylated genes was significantly higher in H pylori -infected pediatric samples than in H pylori -negative pediatric samples (3.4 versus 0.3, P < .001) and in H pylori -infected adult samples than in H pylori -negative adult samples (7.6 versus 0.9, P < .001). Seven genes showed significantly higher methylation levels in H pylori -infected pediatric samples than in H pylori -negative pediatric samples (all values were P < .05). CONCLUSIONS: These results indicate that CpG island hypermethylation occurs in pediatric gastric mucosa in association with H pylori infection and that the genes affected by H pylori -associated hypermethylation were similar in pediatric and adult samples.