esteller davalos merkel villasante

Two birds with one stone: a refined bioinformatic analysis can estimate gene copy-number variations from epigenetic data

A team led by Dr. Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute, has improved the computational identification of potentially druggable gene amplifications in tumors, from epigenetic data. By using this new tool, scientists can have reliable information on the molecular data of a particular tumor, both at the genetics and epigenetics level, even from scarce samples.

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Visita Ministra Diana Morant

The Josep Carreras Leukaemia Research Institute, has been selected by the National Cancer Institute for the Cancer Proteome Project with the support of the Spanish Ministry of Science and Innovation

The Josep Carreras Institute becomes part of the Cancer Proteome project, an international initiative for the study of malignant tumors. It has the support of the Spanish Ministry of Science and Innovation, whose Minister, Diana Morant, visited the Josep Carreras Institute on Thursday and announced a grant of one million euros to promote the project.

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Grup Briones - Sant Pau

Phase I of Europe's first self-produced CAR-T30 clinical trial for Hodgkin's and non-Hodgkin's lymphoma ends

The first trial with a CAR-T immunotherapy drug produced in Sant Pau, a pioneer in Europe, for the treatment of classic Hodgkin's lymphoma and non-Hodgkin T lymphoma CD30 + in relapse or refractory, has successfully completed its Phase I . The project is led by Dr. Javier Briones, Head of the Clinical Hematology Unit of the Hematology Service of the Hospital de Sant Pau and Head of the Cell Immunotherapy and Gene Therapy Research Group of the Research Institute of the Hospital de Sant Pau - IIB-Sant Pau and the Josep Carreras Leukaemia Research Institute.

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A Blood Test allows to differentiate severe COVID-19 from preeclampsia in pregnant women

The researchers team led by Dr. Marta Palomo, from the Josep Carreras Leukaemia Research Institute, and Dr. Fàtima Crispi, from BCNatal-IDIBAPS, has identified indicators which allow to differentiate both pathologies. In the framework of a project funded by the telethon Fundació La Marató of TV3, the outcome of this study opens the door to a more accurate diagnosis for both diseases and a better risk assessment. 

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Recent publications

Genescà, E, González-Gil, C

Latest Contributions of Genomics to T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Cancers 2022 17 May 2022, (14) 2474. Epub 17 May 2022
As for many neoplasms, initial genetic data about T-cell acute lymphoblastic leukemia (T-ALL) came from the application of cytogenetics. This information helped identify some recurrent chromosomal alterations in T-ALL at the time of diagnosis, although it was difficult to determine their prognostic impact because of their low incidence in the specific T-ALL cohort analyzed. Genetic knowledge accumulated rapidly following the application of genomic techniques, drawing attention to the importance of using high-resolution genetic techniques to detect cryptic aberrations present in T-ALL, which are not usually detected by cytogenetics. We now have a clearer appreciation of the genetic landscape of the different T-ALL subtypes at diagnosis, explaining the particular oncogenetic processes taking place in each T-ALL, and we have begun to understand relapse-specific mechanisms. This review aims to summarize the latest advances in our knowledge of the genome in T-ALL. We highlight areas where the research in this subtype of ALL is progressing with the aim of identifying key questions that need to be answered in the medium-long term if this knowledge is to be applied in clinics.
Blecua P, Davalos V, de Villasante I, Merkel A, Musulen E, Coll-SanMartin L, Esteller M

Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary.

Brief Bioinform 6 May 2022, . Epub 6 May 2022
High-throughput genomic technologies are increasingly used in personalized cancer medicine. However, computational tools to maximize the use of scarce tissues combining distinct molecular layers are needed. Here we present a refined strategy, based on the R-package 'conumee', to better predict somatic copy number alterations (SCNA) from deoxyribonucleic acid (DNA) methylation arrays. Our approach, termed hereafter as 'conumee-KCN', improves SCNA prediction by incorporating tumor purity and dynamic thresholding. We trained our algorithm using paired DNA methylation and SNP Array 6.0 data from The Cancer Genome Atlas samples and confirmed its performance in cancer cell lines. Most importantly, the application of our approach in cancers of unknown primary identified amplified potentially actionable targets that were experimentally validated by Fluorescence in situ hybridization and immunostaining, reaching 100% specificity and 93.3% sensitivity.
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Garcia-Prieto CA, Martínez-Jiménez F, Valencia A, Porta-Pardo E

Detection of oncogenic and clinically actionable mutations in cancer genomes critically depends on variant calling tools.

Bioinformatics 5 May 2022, . Epub 5 May 2022
The analysis of cancer genomes provides fundamental information about its aetiology, the processes driving cell transformation or potential treatments. While researchers and clinicians are often only interested in the identification of oncogenic mutations, actionable variants or mutational signatures, the first crucial step in the analysis of any tumor genome is the identification of somatic variants in cancer cells (i.e., those that have been acquired during their evolution). For that purpose, a wide range of computational tools have been developed in recent years to detect somatic mutations in sequencing data from tumor samples. While there have been some efforts to benchmark somatic variant calling tools and strategies, the extent to which variant calling decisions impact the results of downstream analyses of tumor genomes remains unknown.
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Arribas AJ, Napoli S, Cascione L, Sartori G, Barnabei L, Gaudio E, Tarantelli C, Mensah AA, Spriano F, Zucchetto A, Rossi FM, Rinaldi A, De Moura MC, Jovic S, Bordone-Pittau R, Di Veroli A, Stathis A, Cruciani G, Stussi G, Gattei V, Brown JR, Esteller M, Zucca E, Rossi D, Bertoni F

Resistance to PI3κδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis.

Haematologica 28 Apr 2022, . Epub 28 Apr 2022
PI3KPPinhibitors are active in patients with lymphoid neoplasms and a first series of them have been approved for the treatment of multiple types of B-cell lymphoid tumors, including marginal zone lymphoma (MZL). The identification of the mechanisms underlying either primary or secondary resistance is fundamental to optimize the use of novel drugs. Here, we present a model of secondary resistance to PI3Kffinhibitors obtained by prolonged exposure of a splenic MZL cell line to idelalisib. The VL51 cell line was kept under continuous exposure to idelalisib. The study included detailed characterization of the model, pharmacological screens, silencing experiments, validation experiments on multiple cell lines and on clinical specimens. VL51 developed resistance to idelalisib, copanlisib, duvelisib, and umbralisib. An integrative analysis of transcriptome and methylation underlined an enrichment of up-regulated transcripts and lowmethylated promoters in resistant cells, including IL-6/STAT3 and PDGFRA related genes and surface CD19 expression, alongside the repression of the let-7 family miRNAs, of miR-125, miR-130, miR-193 and miR-20. The use of the IL-6R blocking antibody tocilizumab, the STAT3 inhibitor stattic, the LIN28 inhibitor LIN1632, the PDGFR inhibitor masitinib and the anti-CD19 antibody drug conjugate loncastuximab tesirine were active compounds in the resistant cells as single agents and/or in combination with PI3K//inhibition. Findings were validated on additional in vitro lymphoma models and on clinical specimens. A novel model of resistance obtained from splenic MZL allowed the identification of therapeutic approaches able to improve the anti-tumor activity of PI3Kttinhibitors in B-cell lymphoid tumors.
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Cao X, Li W, Wang T, Ran D, Davalos V, Planas-Serra L, Pujol A, Esteller M, Wang X, Yu H

Accelerated biological aging in COVID-19 patients.

Nat Commun 19 Apr 2022, 13 (1) 2135. Epub 19 Apr 2022
Chronological age is a risk factor for SARS-CoV-2 infection and severe COVID-19. Previous findings indicate that epigenetic age could be altered in viral infection. However, the epigenetic aging in COVID-19 has not been well studied. In this study, DNA methylation of the blood samples from 232 healthy individuals and 413 COVID-19 patients is profiled using EPIC methylation array. Epigenetic ages of each individual are determined by applying epigenetic clocks and telomere length estimator to the methylation profile of the individual. Epigenetic age acceleration is calculated and compared between groups. We observe strong correlations between the epigenetic clocks and individual's chronological age (r > 0.8, p < 0.0001). We also find the increasing acceleration of epigenetic aging and telomere attrition in the sequential blood samples from healthy individuals and infected patients developing non-severe and severe COVID-19. In addition, the longitudinal DNA methylation profiling analysis find that the accumulation of epigenetic aging from COVID-19 syndrome could be partly reversed at late clinic phases in some patients. In conclusion, accelerated epigenetic aging is associated with the risk of SARS-CoV-2 infection and developing severe COVID-19. In addition, the accumulation of epigenetic aging from COVID-19 may contribute to the post-COVID-19 syndrome among survivors.
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