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1.
J Clin Immunol ; 43(1): 165-180, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36066697

RESUMEN

Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene (TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene. Both patients presented a history of chronic lymphoproliferation with lymphadenopathies and splenomegaly, cytopenias, and immune dysregulation. We identified the first compound heterozygous patient for TET2 mutations (P1) and the first ALPS-like patient with a monoallelic TET2 mutation (P2). P1 had the most severe form of autosomal recessive disease due to TET2 loss of function resulting in absent TET2 expression and profound increase in DNA methylation. Additionally, the immunophenotype showed some alterations in innate and adaptive immune system as inverted myeloid/plasmacytoid dendritic cells ratio, elevated terminally differentiated effector memory CD8 + T-cells re-expressing CD45RA, regulatory T-cells, and Th2 circulating follicular T-cells. Double-negative T-cells, vitamin B12, and IL-10 were elevated according to the ALPS-like suspicion. Interestingly, the healthy P1's brother carried a TET2 mutation and presented some markers of immune dysregulation. P2 showed elevated vitamin B12, hypergammaglobulinemia, and decreased HDL levels. Therefore, novel molecular defects in TET2 confirm and expand both clinical and immunological phenotype, contributing to a better knowledge of the bridge between cancer and immunity.


Asunto(s)
Síndrome Linfoproliferativo Autoinmune , Dioxigenasas , Neoplasias Hematológicas , Masculino , Humanos , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/genética , Mutación de Línea Germinal , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Mutación/genética , Fenotipo , Vitamina B 12 , Proteínas de Unión al ADN/genética , Dioxigenasas/genética
2.
Hum Mol Genet ; 24(10): 2914-22, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25678551

RESUMEN

Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C>T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases.


Asunto(s)
Predisposición Genética a la Enfermedad , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , Mutación Missense , Tumores Neuroendocrinos/genética , Neoplasias Gástricas/genética , Adenocarcinoma/genética , Adolescente , Adulto , Anciano , Exoma , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Análisis de Secuencia de ADN , Adulto Joven
3.
Mod Pathol ; 27(2): 281-93, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23929267

RESUMEN

We describe a retrospective series of B-cell lymphoproliferative disorders associated with hepatitis C virus infection. In addition to splenic marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, all of which showed some specific features, we found two poorly described groups of cases. The first featured disseminated marginal zone lymphoma without splenic marginal zone lymphoma features, defying the current marginal zone lymphoma classification; the other consisted of monoclonal B lymphocytes in the peripheral blood, bone marrow or other tissues, with no clinical or histological evidence of lymphoma, and exhibiting a pattern that requires proper identification in order to avoid the misdiagnosis of the lymphoma. Diagnosis of hepatitis C virus infection-associated lymphoproliferative disorders requires the integration of clinical, pathological and molecular findings to establish an adequate diagnosis and decide the appropriate therapy to be applied.


Asunto(s)
Hepatitis C/complicaciones , Linfoma de Células B/patología , Linfoma de Células B/virología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Trastornos Linfoproliferativos/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
4.
Blood ; 119(3): e9-e21, 2012 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-22110251

RESUMEN

Nodal marginal zone lymphoma (NMZL) is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed gene expression, miRNA profile, and copy number data from 15 NMZL cases. For comparison, 16 follicular lymphomas (FLs), 9 extranodal marginal zone lymphomas, and 8 reactive lymph nodes and B-cell subtypes were included. The results were validated by quantitative RT-PCR in an independent series, including 61 paraffin-embedded NMZLs. NMZL signature showed an enriched expression of gene sets identifying interleukins, integrins, CD40, PI3K, NF-κB, and TGF-ß, and included genes expressed by normal marginal zone cells and memory B cells. The most highly overexpressed genes were SYK, TACI, CD74, CD82, and CDC42EP5. Genes linked to G(2)/M and germinal center were down-regulated. Comparison of the gene expression profiles of NMZL and FL showed enriched expression of CHIT1, TGFB1, and TACI in NMZL, and BCL6, LMO2, and CD10 in FL. NMZL displayed increased expression of miR-221, miR-223, and let-7f, whereas FL strongly expressed miR-494. Our study identifies new candidate diagnostic molecules for NMZL and reveals survival pathways activated in NMZL.


Asunto(s)
Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Linfoma de Células B de la Zona Marginal/genética , Linfoma Folicular/genética , MicroARNs/genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Linfoma de Células B de la Zona Marginal/diagnóstico , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
5.
Am J Surg Pathol ; 33(5): 730-8, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19194277

RESUMEN

The spleen is frequently involved in B-cell lymphomas other than splenic marginal zone lymphoma. Here we describe a series of follicular lymphoma (FL) cases diagnosed in the spleen, consisting of 32 patients who presented clinically with splenomegaly, and slight or no peripheral lymphadenopathy. The splenic specimen had a micronodular pattern, germinal center cytologic composition, and frequent presence of marginal zone-like cells at the periphery of the nodules. Twenty cases showed absence or only partial/weak bcl2 protein expression, and 12 cases had homogeneous and strong positive bcl2 expression. The incidences of t(14;18)(q32;q21), CD10 expression, low histologic grade, and low proliferative index were significantly more frequent in FL bcl2-positive cases than in FL bcl2-negative cases. Splenic FL cases showed frequent relapses, with an overall survival of 55% at 5 years. No significant differences in survival were found between bcl2-negative and bcl2-positive cases. Splenic FL cases could be divided into 2 main variants: one was similar to classic FL with t(14;18) and CD10 expression, whereas the other was characterized by a higher proliferation index and histologic grade, and was more frequently diagnosed as a disease restricted to the spleen. Recognition of the distinct nature of these tumors should facilitate appropriate studies for determining the best therapy for such cases.


Asunto(s)
Linfoma de Células B/patología , Linfoma Folicular/patología , Neoplasias del Bazo/patología , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Linfoma de Células B/química , Linfoma de Células B/genética , Linfoma de Células B/terapia , Linfoma Folicular/química , Linfoma Folicular/genética , Linfoma Folicular/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neprilisina/análisis , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Recurrencia , Neoplasias del Bazo/química , Neoplasias del Bazo/genética , Neoplasias del Bazo/terapia , Esplenomegalia , Factores de Tiempo , Resultado del Tratamiento
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