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Valdes-Mas R.,University of Oviedo | Bea S.,Hematopathology Unit | Puente D.A.,University of Oviedo | Lopez-Otin C.,University of Oviedo | And 2 more authors.
PLoS ONE | Year: 2012

Exome sequencing constitutes an important technology for the study of human hereditary diseases and cancer. However, the ability of this approach to identify copy number alterations in primary tumor samples has not been fully addressed. Here we show that somatic copy number alterations can be reliably estimated using exome sequencing data through a strategy that we have termed exome2cnv. Using data from 86 paired normal and primary tumor samples, we identified losses and gains of complete chromosomes or large genomic regions, as well as smaller regions affecting a minimum of one gene. Comparison with high-resolution comparative genomic hybridization (CGH) arrays revealed a high sensitivity and a low number of false positives in the copy number estimation between both approaches. We explore the main factors affecting sensitivity and false positives with real data, and provide a side by side comparison with CGH arrays. Together, these results underscore the utility of exome sequencing to study cancer samples by allowing not only the identification of substitutions and indels, but also the accurate estimation of copy number alterations. © 2012 Valdés-Mas et al. Source


Delgado J.,Hospital Clinic | Pereira A.,Hematopathology Unit | Villamor N.,Deparment of Hemostasis and Hemotherapy | Lopez-Guillermo A.,Hospital Clinic | Rozman C.,Josep Carreras Leukemia Research Institute
Haematologica | Year: 2014

The widespread availability of statistical packages has undoubtedly helped hematologists worldwide in the analysis of their data, but has also led to the inappropriate use of statistical methods. In this article, we review some basic concepts of survival analysis and also make recommendations about how and when to perform each particular test using SPSS, Stata and R. In particular, we describe a simple way of defining cut-off points for continuous variables and the appropriate and inappropriate uses of the Kaplan-Meier method and Cox proportional hazard regression models. We also provide practical advice on how to check the proportional hazards assumption and briefly review the role of relative survival and multiple imputation. © 2014 Ferrata Storti Foundation. Source


Montraveta A.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Xargay-Torrent S.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Lopez-Guerra M.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Rosich L.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | And 9 more authors.
Oncotarget | Year: 2014

Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses.The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients. Source


Moros A.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Bustany S.,University of Caen Lower Normandy | Cahu J.,University of Caen Lower Normandy | Saborit-Villarroya I.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | And 5 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Clinical responses to the immmunomodulatory drug lenalidomide have been observed in patients with relapsed/refractory mantle cell lymphoma (MCL), although its mechanism of action remains partially unknown. We investigated whether the expression and subcellular localization of cyclin D1, a major cell-cycle regulator overexpressed in MCL, and the cyclin-dependent kinase inhibitor p27KIP1, could identify MCL cases sensitive to lenalidomide, and whether the compound could modulate cyclin D1/ p27 KIP1 complexes in MCL cells. Experimental Design: MCL primary samples and cell lines were analyzed for subcellular levels of cyclin D1/p27 KIP1 complexes by Western blot, immunohistochemistry, immunoprecipitation, and flow cytometry. Activity of lenalidomide in vitro and its effect on cyclin D1/p27KIP1 complexes were evaluated by realtime PCR, immunoprecipitation, immunofluorescence, and Western blot. In vivo validation was carried out in a mouse xenograft model of human MCL. Results: We found cyclin D1 and p27KIP1 to be coordinately expressed in all the MCL samples tested. Immunoprecipitation analyses and siRNA assays suggested a direct role of cyclin D1 in the regulation of p27KIP1 levels. The nuclear accumulation of both proteins correlated with MCL cell tumorigenicity in vivo, and sensitivity to lenalidomide activity in vitro and in vivo. Lenalidomide mechanism of action relied on cyclin D1 downregulation and disruption of cyclin D1/p27KIP1 complexes, followed by cytosolic accumulation of p27KIP1, cell proliferation arrest, apoptosis, and angiogenesis inhibition. Conclusions: These results highlight a mechanism of action of lenalidomide inMCLcases with increased tumorigenicity in vivo, which is mediated by the dissociation of cyclin D1/p27KIP1 complexes, and subsequent proliferation blockade and apoptosis induction. Clin Cancer Res; 20(2); 393-403.© 2013 AACR. © 2013 American Association for Cancer Research. Source


Salaverria I.,University of Barcelona | Salaverria I.,University of Kiel | Royo C.,University of Barcelona | Carvajal-Cuenca A.,University of Barcelona | And 21 more authors.
Blood | Year: 2013

Cyclin D1- mantle cell lymphomas (MCLs) are not well characterized, in part because of the difficulties in their recognition. SOX11 has been identified recently as a reliable biomarker of MCL that is also expressed in the cyclin D1- variant. We investigated 40 lymphomas with MCL morphology and immunophenotype that were negative for cyclin D1 expression/t(11;14)(q13;q32) but positive for SOX11. These tumors presented clinically with generalized lymphadenopathy, advanced stage, and poor outcome (5-year overall survival, 48%). Chromosomal rearrangements of the CCND2 locus were detected in 55% of the cases, with an IG gene as partner in 18 of 22, in particular with light chains (10 IGK and 5 IGL). No mutations in the phosphorylation motifs of CCND1, CCND2, or CCND3 were detected. The global genomic profile and the high complexity of the 32 cyclin D1- SOX11+ MCL patients analyzed by copy number arrays were similar to the conventional cyclin D1+/SOX11+ MCL. 17p deletions and high Ki67 expression conferred a significantly worse outcome for the patients. This comprehensive characterization of a large series of cyclin D1- MCL patients indicates that these tumors are clinically and biologically similar to the conventional cyclin D1+ MCL and provides a basis for the proper identification and clinical management of these patients. Source

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