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1.
J Pathol ; 250(3): 251-261, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31729028

RESUMEN

Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas, although these lesions have been associated with a significant cancer risk, twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better understand the pathogenesis of TSA. We performed a global quantitative proteome analysis using the label-free quantification (LFQ) method on 44 colorectal adenoma (12 TSAs, 15 CADs, and 17 SSA/Ps) and 17 normal colonic mucosa samples, archived as formalin-fixed paraffin-embedded blocks. Unsupervised consensus hierarchical clustering applied to the whole proteomic profile of the 44 colorectal adenomas identified four subtypes: C1 and C2 were well-individualized clusters composed of all the CADs (15/15) and most of the SSA/Ps (13/17), respectively. This is consistent with the fact that CADs and SSA/Ps are homogeneous and distinct colorectal adenoma entities. In contrast, TSAs were subdivided into C3 and C4 clusters, consistent with the more heterogeneous entity of TSA at the morphologic and molecular levels. Comparison of the proteome expression profile between the adenoma subtypes and normal colonic mucosa further confirmed the heterogeneous nature of TSAs, which overlapped either on CADs or SSA/Ps, whereas CADs and SSAs formed homogeneous and distinct entities. Furthermore, we identified LEFTY1 a new potential marker for TSAs that may be relevant for the pathogenesis of TSA. LEFTY1 is an inhibitor of the Nodal/TGFß pathway, which we found to be one of the most overexpressed proteins specifically in TSAs. This finding was confirmed by immunohistochemistry. Our study confirms that CADs and SSA/Ps form homogeneous and distinct colorectal adenoma entities, whereas TSAs are a heterogeneous entity and may arise from either SSA/Ps or from normal mucosa evolving through a process related to the CAD pathway. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Adenoma/metabolismo , Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Proteoma , Adenoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Colon/patología , Neoplasias Colorrectales/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Adhesión en Parafina , Proteómica
2.
Genes Chromosomes Cancer ; 55(6): 541-8, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26998913

RESUMEN

Gene fusions involving TFE3 defines the "Xp11.2 translocations" subclass of renal cell carcinomas (RCCs) belonging to the MiT family translocation RCC. Four recurrent TFE3 fusion partners were identified to date: PRCC, ASPSCR1, SFPQ, and NONO. Break-apart TFE3 fluorescence in situ hybridization (FISH) on formalin-fixed and paraffin-embedded (FFPE) tissue sections is currently the gold standard for identification of TFE3 rearrangements. Herein, we report a case of RCC with a morphological appearance of Xp11.2 translocation, and positive TFE3 immunostaining. By FISH, the spots constituting the split signal were barely spaced, suggestive of a chromosome X inversion rather than a translocation. We performed RNA-seq from FFPE material to test this hypothesis. RNA-seq suggested a fusion of RBM10 gene exon 17 (Xp11.23) with TFE3 gene exon 5 (Xp11.2). RBM10-TFE3 fusion transcript was confirmed using specific RT-PCR. Our work showed that RNA-Seq is a robust technique to detect fusion transcripts from FFPE material. A RBM10-TFE3 fusion was previously described in single case of Xp11.2 RCC. Although rare, RBM10-TFE3 fusion variant (from chromosome X paracentric inversion), therefore, appears to be a recurrent molecular event in Xp11.2 RCCs. RBM10-TFE3 fusion should be added in the list of screened fusion transcripts in targeted molecular diagnostic multiplex RT-PCR. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carcinoma de Células Renales/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Unión al ARN/genética , Carcinoma de Células Renales/patología , Cromosomas Humanos X , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Masculino , Adhesión en Parafina
3.
Carcinogenesis ; 33(9): 1791-6, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22696594

RESUMEN

Intrahepatic malignant tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and combined hepatocholangiocarcinomas (cHCC-CC), a group of rare and poorly characterized tumours that exhibit both biliary and hepatocytic differentiation. The aim of the study was to characterize the molecular pathways specifically associated with cHCC-CC pathogenesis. We performed a genome-wide transcriptional analysis of 20 histologically defined cHCC-CC and compared them with a series of typical HCC and of CC. Data were analysed by gene set enrichment and integrative genomics and results were further validated in situ by tissue microarray using an independent series of 152 tumours. We report that cHCC-CC exhibit stem/progenitor features, a down-regulation of the hepatocyte differentiation program and a commitment to the biliary lineage. TGFß and Wnt/ß-catenin were identified as the two major signalling pathways activated in cHCC-CC. A ß-catenin signature distinct from that observed in well-differentiated HCC with mutant ß-catenin was found in cHCC-CC. This signature was associated with microenvironment remodelling and TGFß activation. Furthermore, integrative genomics revealed that cHCC-CC share characteristics of poorly differentiated HCC with stem cell traits and poor prognosis. The common traits displayed by CC, cHCC-CC and some HCC suggest that these tumours could originate from stem/progenitor cell(s) and raised the hypothesis of a potential continuum between intrahepatic CC, cHCC-CC and poorly differentiated HCC.


Asunto(s)
Carcinoma Hepatocelular/etiología , Colangiocarcinoma/etiología , Neoplasias Hepáticas/etiología , Células Madre Neoplásicas/patología , Factor de Crecimiento Transformador beta/fisiología , Vía de Señalización Wnt/fisiología , Neoplasias de los Conductos Biliares , Conductos Biliares Intrahepáticos , Carcinoma Hepatocelular/patología , Diferenciación Celular , Colangiocarcinoma/patología , Matriz Extracelular/fisiología , Perfilación de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , Pronóstico , Transducción de Señal/fisiología , Análisis de Matrices Tisulares , beta Catenina/fisiología
4.
Mod Pathol ; 25(2): 197-211, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22080063

RESUMEN

Over the past decade, comprehensive genomic studies demonstrated that leiomyosarcomas and most of the tumors previously labeled as 'malignant fibrous histiocytomas' share complex karyotypes and genomic profiles, and can be referred to as 'sarcomas with complex genomics'. We recently reported a series of 160 sarcomas with complex genomics such as leiomyosarcomas, myxofibrosarcomas, pleomorphic liposarcomas/rhabdomyosarcomas and undifferentiated pleomorphic sarcomas. These tumors present with a frequent loss of chromosome 10 region encompassing the tumor suppressor gene PTEN. In the present study, we assessed PTEN genomic level and protein expression in this large series of sarcomas with complex genomics, as well as activation of downstream pathways. PTEN partial genomic loss was observed in only 46% of tumors, especially in well-differentiated leiomyosarcomas, whereas up to 68% of these tumors demonstrate a loss of protein expression on western blot analysis. Specific discrepancies in PTEN immunohistochemical results suggested bias in this latter technique. PTEN mutations were rare, with only 4 point mutations in the 65 samples studied. Subsequent activation of AKT and mTOR pathways was only observed in 2 out of 3 of PTEN-deleted tumors. On the other hand, RICTOR, a major component of the mTOR complex 2, was significantly overexpressed in well-differentiated leiomyosarcomas. These results, confirmed on tissue micro-array immunohistochemical analysis of 459 sarcomas, could suggest a link between RICTOR overexpression and leiomyosarcomas oncogenesis. As therapeutics directed against the mTOR pathway are assessed in sarcomas, RICTOR overexpression in sarcomas and its links to therapeutic response need to be assessed.


Asunto(s)
Proteínas Portadoras/genética , Diferenciación Celular , Leiomiosarcoma/genética , Liposarcoma/genética , Fosfohidrolasa PTEN/genética , Tumor de Músculo Liso/genética , Serina-Treonina Quinasas TOR/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Proteínas Portadoras/metabolismo , Diferenciación Celular/genética , Hibridación Genómica Comparativa , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Leiomiosarcoma/clasificación , Leiomiosarcoma/metabolismo , Liposarcoma/clasificación , Liposarcoma/patología , Masculino , Persona de Mediana Edad , Músculo Liso/metabolismo , Músculo Liso/patología , Fosfohidrolasa PTEN/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/fisiología , Tumor de Músculo Liso/clasificación , Tumor de Músculo Liso/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Análisis de Matrices Tisulares
6.
J Pathol ; 218(2): 201-9, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19235837

RESUMEN

Solid-pseudopapillary neoplasms (SPNs) are rare human pancreatic neoplasms usually associated with a good prognosis. In contrast to other pancreatic tumours, aberrant activation of the Wnt-beta-catenin pathway appears to be a constant feature in SPN. Aside from activation of the Wnt-beta-catenin pathway, little is known about biological pathways deregulated in SPN. We carried out transcriptome profiling of SPN to gain insights into the pathogenesis of these tumours. As expected, the over-expression of AXIN2, TBX3, SP5 and NOTUM demonstrated activation of the beta-catenin pathway. Members of the Notch pathway (HEY1, HEY2, NOTCH2) were also up-regulated, relative to their expression in ductal adenocarcinomas (DAC) or pancreatic endocrine tumours (PET). Other genes, such as EDN3, HAND2, netrin-G2 and the receptor netrin-G1 ligand, involved in neural crest differentiation, were also identified as altered. Increased levels of SOX10 and TuJ-1 proteins were also indicative of neural-like differentiation. In conclusion, SPN display a complex expression profile, distinct from that observed in PET and DAC and involving both the beta-catenin and Notch pathways, together with expression of neural differentiation markers.


Asunto(s)
Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Tumores Neuroendocrinos/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Pancreáticas/genética , Adolescente , Adulto , Biomarcadores de Tumor , Estudios de Casos y Controles , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Cresta Neural/metabolismo , Tumores Neuroendocrinos/embriología , Neoplasias Pancreáticas/embriología , Receptores Notch/genética , Transducción de Señal/genética , Proteínas Wnt/genética , Adulto Joven , beta Catenina/genética
7.
Virchows Arch ; 477(5): 697-704, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32524184

RESUMEN

Few data are available concerning human papillomavirus (HPV) in early esophageal squamous cell carcinoma (ESCC) in Western population. Our study intended to determine the prevalence of HPV infection and the histological characteristics in such early tumors. A monocentric and retrospective study was conducted including 86 patients with early ESCC treated by endoscopic resection or esophagectomy, from 2012 to 2018. Histopathological prognostic criteria were evaluated. Immunohistochemistry for p16 and p53 and an HPV mRNA in situ hybridization were performed. The tumors were composed of 25 (29%) in situ carcinomas, 21 (24%) intramucosal carcinomas, and 40 (47%) submucosal carcinomas, of which 34 had a deep infiltration (> 200 µm). Emboli, present in 12 cases, were associated with deep infiltration. P16-positive ESCC accounted for 21% of the patients. It was not correlated with active HPV infection as no cases were found to be positive in RISH analysis for RNA detection of this virus. However, there was a correlation between p16 expression and alcohol or tobacco consumption. The only histopathological criterion correlated with p16 positivity was marked inflammatory infiltrate. Local or distant neoplastic recurrence occurred in 25% of patients. Overall survival was 95.8% and local or metastatic recurrence-free survival was 75%. There was a correlation between positive resection margins and tumor recurrence. In contrast to oropharynx carcinoma, our study showed that ESCC were not associated with an active HPV infection, highlighting the negligible role of this virus in early ESCC carcinogenesis in the Western world.


Asunto(s)
Neoplasias Esofágicas/epidemiología , Carcinoma de Células Escamosas de Esófago/epidemiología , Infecciones por Papillomavirus/epidemiología , Anciano , Biomarcadores de Tumor/análisis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/virología , Carcinoma de Células Escamosas de Esófago/secundario , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/virología , Esofagectomía , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Márgenes de Escisión , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasia Residual , Papillomaviridae/genética , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virología , Paris , Prevalencia , ARN Viral/genética , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/análisis
8.
Front Oncol ; 9: 563, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31316915

RESUMEN

IL-35 is an immunosuppressive cytokine of the IL-12 family consisting of two subunits, EBV-induced gene 3 (EBI3) and p35. It has been shown to play a pro-tumor role in murine tumor models, and in various types of human cancer such as colorectal, pancreatic, or liver carcinoma, its expression has been associated with a worse clinical outcome. Here, we show by analyzing gene expression data from public databases and by immunohistochemical studies that IL-35 is overexpressed by tumor cells in diffuse-large B-cell lymphoma (DLBCL) compared to another type of mature aggressive B-cell lymphoma, Burkitt lymphoma. However, while high IL-35 expression was significantly associated with a worse overall survival in DLBCL patients treated with chemotherapy only (cyclophosphamide, doxorubicin, vincristine, prednisone, CHOP), no significant correlation between IL-35 expression levels and the patient outcome was observed in DLBCL patients treated with CHOP combined to rituximab (R-CHOP), the current conventional treatment. In addition, we found that an anti-IL-35 antibody, clone 15k8D10, used to assess IL-35 expression by immunohistochemistry in various human tissues including tumors does not recognize IL-35 heterodimer, nor its individual subunits EBI3 and p35, but cross-reacts with human IgG1, indicating that IL-35 expression in human cancers needs to be re-evaluated.

9.
Proteomics ; 8(18): 3725-34, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18780398

RESUMEN

MALDI mass spectrometers have become popular tools for imaging histological sections. Currently this technology is primarily used for imaging naturally occurring molecules. Here we report on the improvement of TArgeted multiplex MS IMaging (TAMSIM) technology. For TAMSIM we attach photocleavable mass tags to antibodies. Staining histological sections is done analogously to standard immunohistochemical procedures with chemiluminescent or fluorescent detection with the sole difference that multiple antibodies each with a distinct mass tag are used in a single reaction. Mass tags are released from their respective antibodies by a laser pulse at 355 nm without added matrix. After scanning, MS images are created for each tag mass. The enhancements of TAMSIM presented here relate to four elements, the use of an improved generation of tags, their conjugation directly to primary antibodies, the comparison of fresh frozen sections with paraffin embedded ones for the TAMSIM imaging technology and finally, the increase of multiplex detection. Sections of healthy human pancreatic tissue were imaged to visualize different specific biomarkers (synaptophysin, chromogranin, insulin, calcitonin, somatostatin) in neuroendocrine cells of Langerhans islets. The aim was to localize these biomarkers on the tissue sections simultaneously.


Asunto(s)
Páncreas/metabolismo , Biomarcadores/metabolismo , Humanos , Inmunohistoquímica/métodos , Células de Langerhans/metabolismo , Páncreas/citología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Análisis de Matrices Tisulares/métodos
10.
J Clin Endocrinol Metab ; 93(10): 4135-40, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18647815

RESUMEN

BACKGROUND: The Wnt/beta-catenin and cAMP signaling pathways play an important role in adrenal cortex tumorigenesis. Somatic activating mutations of the beta-catenin gene (CTNNB1) are the most frequent genetic defects identified both in adrenocortical adenomas (ACAs) and adrenocortical cancers (ACCs). PRKAR1A mutations leading to cAMP pathway dysregulation are observed in primary pigmented nodular adrenocortical diseases (PPNADs) and some sporadic ACAs. OBJECTIVE: The objective of the investigation was to study Wnt/beta-catenin dysregulation in adrenocortical tumors (ACTs) with cAMP pathway genetic alteration and search for secondary CTNNB1 somatic mutations in heterogeneous tumors. PATIENTS AND METHODS: Nine PPNADs, including five with macronodules, three ACAs with PRKAR1A somatic mutations, and one heterogeneous tumor with ACC developed within an ACA, were studied by immunohistochemistry and DNA sequencing. RESULTS: beta-Catenin accumulation was observed in all PPNADs, ACAs with PRKAR1A mutations, and the ACC component of the heterogeneous tumor. CTNNB1 somatic activating mutations were found in the macronodule of two of the five macronodular PPNADs, in one ACA with a PRKAR1A somatic mutation, and in the malignant part of the heterogeneous ACT. CONCLUSIONS: The Wnt/beta-catenin pathway is activated in PPNADs and ACAs with PRKAR1A mutations, suggesting a cross talk between the cAMP and Wnt/beta-catenin pathways in ACT development. In addition, the occurrence as an additional hit of a CTNNB1 somatic mutation is associated with larger or more aggressive ACTs. This underlines the importance of the Wnt/beta-catenin pathway in adrenal cortex tumorigenesis and the importance of genetic accumulation in the progression of ACTs.


Asunto(s)
Adenoma/genética , Neoplasias de la Corteza Suprarrenal/genética , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Mutación , Transducción de Señal/genética , Proteínas Wnt/genética , beta Catenina/genética , Adenoma/metabolismo , Adenoma/patología , Adolescente , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Adulto , Anciano , Anciano de 80 o más Años , Niño , AMP Cíclico/metabolismo , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/fisiología , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación/fisiología , Invasividad Neoplásica , Carga Tumoral/genética , beta Catenina/metabolismo
11.
J Leukoc Biol ; 101(6): 1289-1300, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27677834

RESUMEN

IL-27 regulates immune responses as well as hematopoiesis and bone remodeling, but its cellular sources in the bone remain unknown. In this study, we investigated whether osteoclasts and osteoblasts-the 2 cell types orchestrating bone homeostasis-could be a source of IL-27 and identified stimuli that induce its expression in vitro. We observed that human monocyte-derived osteoclasts expressed a broader range of TLRs than did human primary osteoblasts and that both cell types exhibited a differential induction of IL-27 expression in response to TLR or cytokine stimulation. Whereas several TLR agonists, notably TLR4 and TLR7/8 agonists, induced substantial expression of IL-27 by osteoclasts, stimulation of osteoblasts with agonists of TLR3 and/or TLR4-the 2 TLRs selectively expressed by these cells-resulted in no or low IL-27 expression. In addition, IL-27 increased TLR3 expression in osteoclasts and enhanced poly(I:C)-mediated induction of IL-27 in these cells. IFN-γ, when combined with either IL-1ß plus TNF-α, IL-11, or CNTF, induced significant levels of IL-27 in osteoclasts but not in osteoblasts. In the latter cells, the addition of type I IFN, together with proinflammatory cytokines, was necessary to induce substantial levels of IL-27. Immunohistochemical studies of inflamed and remodeling bone tissue, including cases of infectious osteomyelitis and bone metastases, provided evidence that osteoclasts, osteoblasts, and occasionally osteocytes or chondrocytes, could express IL-27 in situ. This autocrine production of IL-27 by TLR- or cytokine-activated bone cells might constitute a negative-feedback mechanism to limit bone erosion and to dampen T cell-mediated immune pathology during bone inflammation.


Asunto(s)
Huesos/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Interleucinas/metabolismo , Monocitos/metabolismo , Osteoclastos/metabolismo , Receptores Toll-Like/metabolismo , Neoplasias Óseas/inmunología , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Huesos/citología , Huesos/inmunología , Diferenciación Celular , Células Cultivadas , Humanos , Inflamación/inmunología , Inflamación/patología , Monocitos/citología , Monocitos/inmunología , Osteoclastos/citología , Osteoclastos/inmunología , Osteosarcoma/inmunología , Osteosarcoma/metabolismo , Osteosarcoma/patología
12.
Reprod Sci ; 23(9): 1258-68, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26994067

RESUMEN

The current study aimed to identify and validate an applicable immunohistochemistry panel including Ki-67, c-MYC, estrogen receptor-α (ER-α), and progesterone receptor isoforms A/B (PR-A/B) in correlation with clinicopathological parameters in patients affected by deep infiltrating endometriosis. Tissue microarrays were prepared from a cohort of 113 patients. Phenotypic profile of the panel molecules was evaluated in glands and stroma in parallel with microvessels and stroma density measurements. Principal component analysis was performed on 8 immunohistochemical variables, 2 histological variables, and 8 subgroups of clinical parameters. The immunohistochemical profiling showed consistent Ki-67 immunostaining in 17.9% of the samples and c-MYC in 83.1%, while intense ER-α immunoreactivity was detected in 84% of the samples and PR-A/B isoforms in 24.1% of them. The combination of clinical parameters and tissue phenotype allowed a stratification of endometriosis-affected patients. Such novel phenotypical and clinical correlation could be helpful in the future studies for a better stratification of the disease aiming at a personalized patient care.


Asunto(s)
Endometriosis/metabolismo , Endometriosis/patología , Adulto , Proteínas de Unión al ADN/metabolismo , Endometriosis/diagnóstico , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Microvasos/metabolismo , Fenotipo , Receptores de Progesterona/metabolismo , Análisis de Matrices Tisulares , Factores de Transcripción/metabolismo
13.
Eur J Endocrinol ; 170(3): 385-91, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24347427

RESUMEN

CONTEXT: Adrenocortical carcinoma (ACC) is a rare disease with a poor overall outcome. Transcriptome analysis identified two groups of ACCs with different prognosis. In aggressive ACCs, somatic mutations of the tumor suppressor gene TP53 and the proto-oncogene ß-catenin are detected in 50% of cases. For the remaining aggressive ACCs and for the group with a better prognosis, molecular alterations are unknown. OBJECTIVE: To identify new molecular actors driving adrenal tumorigenesis. EXPERIMENTAL DESIGN: Analysis by mass array of 374 mutations among 32 common oncogenes or tumor suppressor genes was performed on the tumoral DNA of 26 ACCs, using Sequenom OncoCarta Panels. RESULTS: Four mutations were identified, two previously known ß-catenin mutations and one alteration in two other genes: JAK3 and retinoblastoma gene (RB1). The JAK3 alteration was found in leukocyte DNA and therefore considered as a polymorphism and not a somatic event. The full RB1 tumor suppressor gene was subsequently sequenced in a cohort of 49 ACCs (26 ACCs from the 'OncoCarta cohort' and 23 other ACCs): three somatic mutations were identified, all in the poor-outcome ACC group. By immunohistochemistry, a loss of the retinoblastoma protein (pRb) was found exclusively in aggressive ACCs in 27% of cases (seven out of 26), three of them with an inactivating RB1 mutation. Among the seven pRb-negative ACCs, five had an allele loss at the RB1 locus. CONCLUSIONS: Parallel analysis of somatic mutations among known cancer genes allowed us to identify RB1 as a new actor in aggressive ACCs. These results suggest a prognostic significance of pRb expression loss in ACCs.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Proteína de Retinoblastoma/genética , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Perfilación de la Expresión Génica , Humanos , Janus Quinasa 3/genética , Mutación , Proto-Oncogenes Mas , Proteína p53 Supresora de Tumor/genética , beta Catenina/genética
14.
PLoS One ; 8(10): e75694, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24130734

RESUMEN

Interleukin (IL)-27 is a cytokine of the IL-12 family that displays either immunostimulatory or immunosuppressive functions depending on the context. In various murine tumor models including melanoma models, ectopic expression of IL-27 has been shown to play an anti-tumoral role and to favor tumor regression. In this study, we investigated whether IL-27 might play a role in the development of melanoma in humans. We analyzed the in situ expression of IL-27 in melanocytic lesions (n = 82) representative of different stages of tumor progression. IL-27 expression was not observed in nevus (n = 8) nor in in situ melanoma (n = 9), but was detected in 28/46 (61%) cases of invasive cutaneous melanoma, notably in advanced stages (19/23 cases of stages 3 and 4). In most cases, the main source of IL-27 was tumor cells. Of note, when IL-27 was detected in primary cutaneous melanomas, its expression was maintained in metastatic lesions. These in situ data suggested that the immunosuppressive functions of IL-27 may dominate in human melanoma. Consistent with this hypothesis, we found that IL-27 could induce suppressive molecules such as PD-L1, and to a lesser extent IL-10, in melanoma cells, and that the in situ expression of IL-27 in melanoma correlated with those of PD-L1 and IL-10.


Asunto(s)
Interleucina-27/metabolismo , Melanoma/metabolismo , Nevo Pigmentado/metabolismo , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Citometría de Flujo , Humanos , Inmunohistoquímica , Interleucina-10/metabolismo , Interleucina-27/farmacología , Neoplasias Cutáneas , Melanoma Cutáneo Maligno
15.
Lung Cancer ; 76(3): 309-15, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22153831

RESUMEN

EML4-ALK adenocarcinomas constitute a new molecular subgroup of lung tumours that respond very well to crizotinib, an ALK inhibitor. However, the diagnosis of ALK rearrangement in lung cancer is challenging. The aim of this study was to compare the diagnostic accuracy of five different methods in a series of 20 EGFR(wt/wt) lung adenocarcinomas from non- or light- smokers. Multiplex RT-PCR was considered as gold standard and identified four ALK-rearranged tumours among the 20 tested tumours. qRT-PCR got an interpretability rate of 100% and accurately typed all 20 tumours. qRT-PCR from corresponding formalin-fixed paraffin-embedded (FFPE) specimens got an interpretability rate of 65%. Out of the four previously identified ALK-rearranged cases, three were interpretable and two were retrieved using FFPE qRT-PCR. ALK break-apart FISH got an interpretability rate of 60% and accurately typed all of the twelve remaining cases. Anti-ALK immunohistochemistry (IHC) accurately typed all twenty tumours using a cut-off value of strong staining of 100% tumour cells. The 16 non ALK-rearranged tumours got no/light staining in 13 cases, and a moderate staining of 80-100% tumour cells in 3 cases. We then analysed four solid signet-ring lung adenocarcinomas. FFPE qRT-PCR, FISH and immunohistochemistry were concordant in three cases, with positive and negative results in respectively one and two cases. The fourth case, which was positive by FISH and immunohistochemistry but negative by RT-PCR, was shown to have a non-EML4-ALK ALK-rearrangement. As various factors such as RNA quality, fixation quality and type of ALK rearrangement may impede ALK screening, we propose a combined FISH/molecular biology diagnostic algorithm in which anti-ALK immunohistochemistry is used as a pre-screening step.


Asunto(s)
Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinasas Receptoras/genética , Translocación Genética , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Población Blanca
16.
Dig Liver Dis ; 43(12): 971-4, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21893434

RESUMEN

BACKGROUND: Acinar cell carcinomas of the pancreas are rare neoplasms. Usually diagnosed at an advanced stage, in general they are large solid pancreatic tumours with an average size of more than 10 cm. AIMS AND RESULTS: We report 3 cases of acinar cell carcinomas involving the peripancreatic lymph nodes, the liver hilum and the colon respectively, without clinical or pathological evidence of pancreatic tumours. These highly cellular neoplasms showed a predominantly acinar cell differentiation intermingled with a ductal component, with intracellular or extracellular mucin production by at least 25% of tumour cells. In addition, one case showed endocrine differentiation. Diffuse immunoreactivity for acinar enzymes trypsin and chymotrypsin was present in all cases. CONCLUSION: The occurrence of acinar cell carcinomas outside the pancreas underlines the notion that acinar cell carcinomas may originate in extrapancreatic sites and probably develop from heterotopic or metaplastic pancreatic foci present along the biliary tract.


Asunto(s)
Carcinoma de Células Acinares/patología , Neoplasias Hepáticas/secundario , Neoplasias Pancreáticas/patología , Neoplasias Retroperitoneales/secundario , Anciano , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/secundario , Carcinoma de Células Acinares/cirugía , Quimotripsina/análisis , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirugía , Tripsina/análisis
17.
J Invest Dermatol ; 131(9): 1896-905, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21654834

RESUMEN

Dacarbazine (DTIC) is the standard first-line drug for advanced stage melanoma, but it induces objective clinical responses in only 15% of patients. This study was designed to identify molecular changes specifically induced by treatment in chemo-sensitive lesions. Using global transcriptome analysis and immunohistochemistry, we analyzed cutaneous metastases resected from patients with melanoma before and after DTIC treatment. The treatment induced similar functional changes in different lesions from the same patient. Stromal and immune response-related genes were the most frequently upregulated, particularly in lesions that responded to treatment by stabilizing or regressing. T-cell infiltration and enhanced major histocompatibility complex class II expression were observed in a subset of patients. Stable, chemo-sensitive lesions exhibited activation of genetic programs related to extracellular matrix remodeling, including increased expression of secreted protein acidic and rich in cysteine (SPARC) by tumor cells. These events were associated with local response to treatment and with superior survival in our group of patients. In contrast, SPARC expression was downregulated in lesions resistant to DTIC. Thus, chemotherapy drugs originally selected for their direct cytotoxicity to tumor cells may also influence disease progression by inducing changes in the tumor microenvironment.


Asunto(s)
Dacarbazina/farmacología , Linfocitos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Células del Estroma/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/farmacología , Biopsia , Progresión de la Enfermedad , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Técnicas In Vitro , Estimación de Kaplan-Meier , Linfocitos/patología , Masculino , Melanoma/genética , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Osteonectina/genética , Osteonectina/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Células del Estroma/patología , Adulto Joven
18.
Clin Cancer Res ; 17(2): 328-36, 2011 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-21088256

RESUMEN

PURPOSE: Activation of the Wnt/ß-catenin signaling pathway is frequent in adrenocortical carcinoma (ACC) and might be associated with a more aggressive phenotype. The objective of this study was to assess the prognostic value of ß-catenin immunohistochemistry and CTNNB1 (ß-catenin gene)/APC (adenomatous polyposis coli gene) mutations in patients with resected primary ACC. EXPERIMENTAL DESIGN: In 79 patients with resected primary ACC from a French cohort (Cochin-COMETE), ß-catenin expression was assessed on tumor specimens by immunohistochemistry. For patients with available DNA (n = 49), CTNNB1, and APC hotspot (mutation cluster region), were sequenced. Association between these results and the clinicopathologic characteristics of the ACC and overall and disease-free survival were studied. Results were confirmed on a tissue microarray from an independent multicentric cohort of 92 ACC from Germany (German-ENSAT cohort). RESULTS: In the Cochin-COMETE cohort, the presence of a ß-catenin nuclear staining was significantly associated with a higher ENSAT tumor stage (i.e., stages III and IV), higher Weiss score, more frequent necrosis, mitoses, and CTNNB1/APC mutations. ß-Catenin nuclear staining and the presence of CTNNB1/APC mutations were both associated with decreased overall and disease-free survival, and were independent predictive factors of survival in multivariate analysis. The same results were observed in the German-ENSAT cohort. CONCLUSIONS: Wnt/ß-catenin activation, confirmed by the presence of ß-catenin nuclear staining, is an independent prognostic factor of overall and disease-free survival in patients with resected primary ACC.


Asunto(s)
Carcinoma Corticosuprarrenal/metabolismo , beta Catenina/metabolismo , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/mortalidad , Adulto , Supervivencia sin Enfermedad , Femenino , Genes APC , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutación , Resultado del Tratamiento , beta Catenina/genética
19.
J Clin Endocrinol Metab ; 96(2): E419-26, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21084400

RESUMEN

BACKGROUND: Abnormal ß-catenin immunohistochemistry and mutations of the ß-catenin gene (CTNNB1) have been reported in adrenocortical adenomas (ACAs), but the frequencies of these defects and the phenotype of such tumors have not been clearly determined. OBJECTIVE: The objective of the study was to describe the Wnt/ß-catenin pathway alterations in 100 ACAs and their association with clinicopathological characteristics. PATIENTS AND METHODS: One hundred consecutive ACAs (excluding Conn's adenomas) were studied clinically by ß-catenin immunohistochemistry and direct sequencing of CTNNB1. RESULTS: Thirty-five ACAs were nonsecreting adenomas (NSAs), 19 were subclinical cortisol secreting adenomas (SCSAs), and 46 were cortisol secreting adenomas (CSAs). Fifty-one tumors had abnormal cytoplasmic and/or nuclear ß-catenin immunohistochemical staining, indicating Wnt/ß-catenin pathway alteration. Thirty-six tumors showed CTNNB1 mutations, which all showed abnormal immunohistochemical ß-catenin accumulation. Among the 64 nonmutated tumors, only 15 (23%) showed cytoplasmic and/or nuclear ß-catenin staining (P < 0.0001). Tumors with CTNNB1 mutations were predominantly nonsecreting (61% NSAs, 22% SCSAs, 16% CSAs) whereas nonmutated tumors were predominantly secreting (20% NSAs, 17% SCSAs, 62% CSAs) (P < 0.0001). Mean tumor size and weight were, respectively, 4.2 cm (± 1.3) and 28.4 g (± 21.4) for tumors with CTNNB1 mutations vs. 3.4 cm (± 0.9) and 18.2 g (± 8.2) for nonmutated tumors (P < 0.01). CONCLUSIONS: Abnormal cytoplasmic and/or nuclear ß-catenin immunohistochemical staining occurs in about half of ACAs. This suggests the activation of the Wnt/ß-catenin pathway, which could be explained by activating mutations of CTNNB1 in 70% of the cases. CTNNB1 mutations are mainly observed in larger and nonsecreting ACAs, suggesting that the Wnt/ß-catenin pathway activation is associated with the development of less differentiated ACAs.


Asunto(s)
Adenoma/genética , Neoplasias de la Corteza Suprarrenal/genética , Hidrocortisona/metabolismo , Mutación/genética , Mutación/fisiología , Transducción de Señal/genética , Proteínas Wnt/genética , beta Catenina/genética , Adenoma/metabolismo , Adenoma/patología , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Adulto , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Fenotipo , ARN Neoplásico/genética
20.
Clin Cancer Res ; 16(21): 5133-41, 2010 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-20978149

RESUMEN

PURPOSE: In adrenocortical tumors (ACT), Wnt/ß-catenin pathway activation can be explained by ß-catenin somatic mutations only in a subset of tumors. ACT is observed in patients with familial adenomatous polyposis (FAP) with germline APC mutations, as well as in patients with Beckwith-Wiedemann syndrome with Wilms' tumors reported to have WTX somatic mutations. Both APC and WTX are involved in Wnt/ß-catenin pathway regulation and may play a role in ACT tumorigenesis. The aim of this study was to report if APC and WTX may be associated with FAP-associated and sporadic ACT. EXPERIMENTAL DESIGN: ACTs from patients with FAP and sporadic adrenocortical carcinomas (ACC) with abnormal ß-catenin localization on immunohistochemistry but no somatic ß-catenin mutations were studied. APC was analyzed by denaturing high-performance liquid chromatography followed by direct sequencing and by multiplex ligation-dependent probe amplification when allelic loss was suspected. WTX was studied by direct sequencing. RESULTS: Four ACTs were observed in three patients with FAP and were ACC, adrenocortical adenoma, and bilateral macronodular adrenocortical hyperplasia, all with abnormal ß-catenin localization. Biallelic inactivation of APC was strongly suggested by the simultaneous existence of somatic and germline alterations in all ACTs. In the 20 sporadic ACCs, a silent heterozygous somatic mutation as well as a rare heterozygous polymorphism in APC was found. No WTX mutations were observed. CONCLUSIONS: ACT should be considered a FAP tumor. Biallelic APC inactivation mediates activation of the Wnt/ß-catenin pathway in the ACTs of patients with FAP. In contrast, APC and WTX genetic alterations do not play a significant role in sporadic ACC.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Silenciador del Gen , Genes APC , Proteínas Adaptadoras Transductoras de Señales , Poliposis Adenomatosa del Colon/complicaciones , Poliposis Adenomatosa del Colon/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/complicaciones , Carcinoma Corticosuprarrenal/metabolismo , Adulto , Anciano , Análisis Mutacional de ADN , Familia , Femenino , Frecuencia de los Genes , Silenciador del Gen/fisiología , Humanos , Masculino , Persona de Mediana Edad , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
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