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 2022High-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.
More informationGarcia-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 2022The 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.
More informationArribas 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 2022PI3KPPinhibitors 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.
More informationCao 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 2022Chronological 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.
More informationFerrer G, Álvarez-Errico D, Esteller M
Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer.
J Natl Cancer Inst 19 Apr 2022, . Epub 19 Apr 2022Adoptive cell therapy (ACT) constitutes a major breakthrough in cancer management that has expanded in the past years due to impressive results showing durable and even curative responses for some patients with hematological malignancies. ACT leverages antigen specificity and cytotoxic mechanisms of the immune system, particularly relying on the patient´s T lymphocytes to target and eliminate malignant cells. This personalized therapeutic approach exemplifies the success of the joint effort of basic, translational and clinical researchers that has turned the patient´s immune system into a great ally in the search for a cancer cure. Adoptive cell therapies are constantly improving to reach a maximum beneficial clinical response. Despite being very promising therapeutic options for certain types of cancers, mainly melanoma and hematological malignancies, these individualized treatments still present several shortcomings including elevated costs, technical challenges, management of adverse side effects and a limited population of responder patients. Thus, it is crucial to discover and develop reliable and robust biomarkers to specifically and sensitively pinpoint the patients that will benefit the most from ACT, as well as those that are at higher risk of developing potentially serious toxicities. Although unique readouts of infused cell therapy success have not yet been identified, certain characteristics from the adoptive cells, the tumor and/or the tumor microenvironment have been recognized to predict patients' outcome upon ACT. Here, we comment on the importance of biomarkers to predict ACT chances of success to maximize efficacy of treatments and increase patients' survival.
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