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1.
Blood ; 128(23): 2666-2670, 2016 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-27670424

RESUMEN

We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.


Asunto(s)
Biomarcadores de Tumor/genética , Eliminación de Gen , Proteínas I-kappa B/genética , Linfoma de Células B , Neoplasias del Mediastino , Proteínas Proto-Oncogénicas/genética , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma de Células B/genética , Linfoma de Células B/mortalidad , Masculino , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/mortalidad , Persona de Mediana Edad , Tasa de Supervivencia
2.
Am J Hematol ; 92(7): 689-694, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28378885

RESUMEN

Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell-free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite-treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03-55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80-50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene-specific methylation data. This analysis shows that global hypomethylation co-occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker.


Asunto(s)
Biomarcadores de Tumor , Metilación de ADN , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/mortalidad , Adulto , Anciano , Biopsia , Análisis por Conglomerados , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Proteínas Quinasas Asociadas a Muerte Celular/genética , Epigénesis Genética , Femenino , Humanos , Estimación de Kaplan-Meier , Elementos de Nucleótido Esparcido Largo , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Regiones Promotoras Genéticas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos
3.
Acta Neuropathol Commun ; 4: 40, 2016 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-27101868

RESUMEN

Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P < 0.0001. TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This study suggests that disruption of the p53-pathway by MUT-TP53in hotspot/direct DNA contact codons is predictive of outcome in CCT-treated PCNSL patients, and concomitant MUT-TP53 and MIR34A methylation are associated with poor PFS.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central , Linfoma , Mutación/genética , Farmacogenética , Proteína p53 Supresora de Tumor/genética , Análisis de Varianza , Antígenos CD/metabolismo , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/mortalidad , Metilación de ADN/genética , Análisis Mutacional de ADN , Proteínas Quinasas Asociadas a Muerte Celular/genética , Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Dinamarca , Femenino , Humanos , Linfoma/tratamiento farmacológico , Linfoma/genética , Linfoma/mortalidad , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
4.
Appl Immunohistochem Mol Morphol ; 23(3): 188-95, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25265435

RESUMEN

OncomiRs miR-21 and miR-155 have been linked to lymphomagenesis, but information on their implication in diffuse large B-cell lymphoma (DLBCL) is limited. Here, we used locked nucleic acid-based in situ hybridization (ISH) detection techniques on formalin-fixed paraffin-embedded DLBCL tissue samples to identify miR-155 and miR-21 at the cellular level in 56 patients diagnosed with DLBCL, and compared them to miR array data. miR-155 was observed in tumor cells in 19/56 (33.9%) of the samples evaluated by ISH. miR-21 was localized to the stromal compartment in 41/56 (73.2%). A subset of these, 16/56 (28.6%), also showed labeling in tumor cells. When comparing ISH-scores and miR array data, miR-155 in tumor cells, identified by ISH, was associated with miR-155 expression in miR array data (P=0.030). Equally, miR-21 expression by miR array data were highly associated with miR-21 ISH-scores in the stromal cells (P=0.002), whereas no association between miR array data and ISH of miR-21 in tumor cells was observed (P=0.673). We found no association of miR-155 and miR-21 with overall survival or germinal center B-cell-like (GCB) versus non-GCB-like subtypes of DLBCL. In conclusion, miR-ISH added to the biological interpretation of miR expression in DLBCL compared with miR array data, but miR-155 and miR-21 ISH did not add prognostic information in this series.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/metabolismo , MicroARNs/biosíntesis , ARN Neoplásico/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Células del Estroma/metabolismo , Células del Estroma/patología
5.
JAMA Ophthalmol ; 133(2): 165-73, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25393033

RESUMEN

IMPORTANCE: The clinical features of diffuse large B-cell lymphoma (DLBCL) subtype of ocular adnexal lymphoma have not previously been evaluated in a large cohort to our knowledge. OBJECTIVE: To investigate the clinical features of ocular adnexal DLBCL (OA-DLBCL). DESIGN, SETTING, AND PARTICIPANTS: This retrospective international cooperative study involved 6 eye cancer centers. During 30 years, 106 patients with OA-DLBCL were identified, and 6 were excluded from the study. The median follow-up period was 52 months. MAIN OUTCOMES AND MEASURES: Overall survival, disease-specific survival (DSS), and progression-free survival were the primary end points. RESULTS: One hundred patients with OA-DLBCL were included in the study (median age, 70 years), of whom 54 (54.0%) were female. The following 3 groups of patients with lymphoma could be identified: primary OA-DLBCL (57.0%), OA-DLBCL and concurrent systemic lymphoma (29.0%), and ocular adnexal lymphoma relapse of previous systemic lymphoma (14.0%). Of 57 patients with primary OA-DLBCL, 53 (93.0%) had Ann Arbor stage IE disease, and 4 (7.0%) had Ann Arbor stage IIE disease. According to the TNM staging system, 43 of 57 (75.4%) had T2 tumors. Among all patients, the most frequent treatments were external beam radiation therapy with or without surgery (31.0%) and rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, prednisone (CHOP) or rituximab-CHOP-like chemotherapy with or without external beam radiation therapy (21.0%). The 5-year overall survival among the entire cohort was 36.0% (median, 3.5 years; 95% CI, 2.5-4.5 years). Relapse occurred in 43.9% (25 of 57) of patients with primary OA-DLBCL. Increasing T category of the TNM staging system was predictive of DSS (P = .04) in primary OA-DLBCL, whereas the Ann Arbor staging system was not. However, when taking all 100 patients into account, Ann Arbor stage was able to predict DSS (P = .01). Women had a longer median DSS than men (9.8 years; 95% CI, 1.9-17.7 years vs 3.3 years; 95% CI, 1.6-5.0; P = .03). CONCLUSIONS AND RELEVANCE: Most patients with primary OA-DLBCL were seen with Ann Arbor stage IE and TNM T2 disease. The 5-year overall survival was between 2.5 and 4.5 years, which is the 95% CI around the median of 3.5 years in this cohort. Increasing T category appears to be associated with decreased DSS among patients with primary OA-DLBCL. When taking all patients into account, sex and Ann Arbor stage also seem to be DSS predictors.


Asunto(s)
Neoplasias del Ojo/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Niño , Preescolar , Terapia Combinada , Diagnóstico Diferencial , Supervivencia sin Enfermedad , Neoplasias del Ojo/mortalidad , Neoplasias del Ojo/terapia , Femenino , Estudios de Seguimiento , Salud Global , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Adulto Joven
6.
APMIS ; 122(9): 750-4, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24372587

RESUMEN

Early determination of malignancy grade and biomarkers in primary breast cancer is important when planning the treatment with neoadjuvant therapy and breast-conserving surgery. The aim of this study was to assess the reliability of malignancy grade on core needle biopsies, and to compare the concordance of ER and HER2 status on core needle biopsies vs surgical specimens. Eighty-nine patients with invasive ductal or lobular carcinoma were included. Malignancy grade was upgraded by one degree in 23.0%. The mitotic count had most impact on the malignancy grade, and may be underestimated on core needle biopsies compared with surgical specimens. ER status was concordant in core needle biopsies and surgical specimens in 98.0%, but should be repeated when doubtfully negative. HER2 status was concordant in 84.0% prior to FISH-HER2. Including FISH-HER2 data, the core needle biopsies showed a final total concordance of 95.4%. In conclusion, ER and HER2 are useful markers in core needle biopsies, providing a reliable base for preoperative decisions in neoadjuvant chemotherapy, and may be omitted on surgical specimens with certain precautions and exceptions. Determination of malignancy grade should be repeated on surgical specimens, and one should be aware of underestimation on core needle biopsies.


Asunto(s)
Biopsia con Aguja Gruesa/métodos , Neoplasias de la Mama/diagnóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Mama/cirugía , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor
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