Ignacio Varela

Instituto de Biomedicina y Biotecnología de Cantabria

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Antonio Agraz-Doblás

Instituto Maimónides de Investigación Biomédica de Córdoba

Pablo Menéndez

Josep Carreras Leukaemia Research Institute

George S. Vassiliou

Cambridge University Hospitals NHS Foundation Trust

P. Andrew Futreal

The University of Texas MD Anderson Cancer Center

Thaidy Moreno-Rodriguez

UCSF Helen Diller Family Comprehensive Cancer Center

Roland Rad

Technical University of Munich

Clara Bueno

Josep Carreras Leukaemia Research Institute

Peter J. Campbell

Wellcome Sanger Institute

Michael R. Stratton

Wellcome Sanger Institute

Juan Cadiñanos

Instituto de Medicina Genómica

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Wellcome Sanger Institute

161

University of Cambridge

Harvard University

Consejo Superior de Investigaciones Científicas

Universidad de Cantabria

Cancer Research UK

Instituto de Salud Carlos III

Marqués de Valdecilla University Hospital

University College London

Technical University of Munich

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Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells

Nature (2011)

Kosuke Yusa S. Tamir Rashid Hélène Strick‐Marchand Ignacio Varela Pei-Qi Liu

Zinc finger nuclease

Gene targeting

Regenerative Medicine

10.1038/nature10424

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Citations (636)

Technical and functional standards and implementation of a clinical information system in intensive care units

Medicina Intensiva (English Edition) (2011)

V. Gómez Tello J. Alvarez A. Núñez Reiz José Ángel González Sánchez A. Hernández Abadía de Barbará

Workgroup

10.1016/j.medine.2011.12.001

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Citations (15)

JAK2 V617F hematopoietic clones are present several years prior to MPN diagnosis and follow different expansion kinetics

Blood Advances (2017)

Thomas McKerrell Naomi Park Jianxiang Chi Grace Collord Thaidy Moreno-Rodriguez

JAK2 V617F

Myeloproliferative Disorders

Janus kinase 2

Hematologic Neoplasms

10.1182/bloodadvances.2017007047

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Citations (50)

Integrative methylome-transcriptome analysis unravels cancer-cell vulnerabilities in infant MLL-rearranged B-ALL (Datasets and additional tables))

Zenodo (CERN European Organization for Nuclear Research) (2021)

Juan Ramón Tejedor Clara Bueno Meritxell Vinyoles Paolo Petazzi Antonio Agraz-Doblás

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicated by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may significantly contribute to its leukemogenesis. We have extensively characterized the DNA methylome and the transcriptome lansdcape of 40 patients with de novo MLL rearranged (MLLr) and non-MLLr iB-ALL leukemias uniformly treated according to Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control. Further methylome-transcriptome integration identified consistent cancer-cell vulnerabilities, revealed a robust iB-ALL-specific gene expression-correlating dmCpG signature and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Pharmacological inhibition or functional ablation of AP-1 activity resulted in dramatic in vitro and in vivo leukemia proliferation defects, providing rationale for new potential therapeutic avenues in iB-ALL. This dataset contains information related to dataframes, databases, scripts and supplementary material mentioned in the original manuscript.

10.5281/zenodo.3695640

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Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation

Leukemia (2013)

Nerea Martı́nez Carmen Almaráz José P. Vaqué Ignacio Varela Sophia Derdak

Exome

Aggressive lymphoma

10.1038/leu.2013.365

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Citations (101)

Somatic structural rearrangements in genetically engineered mouse mammary tumors

Genome biology (2010)

Ignacio Varela Christiaan Klijn P. J. Stephens Laura Mudie Lucy Stebbings

Here we present the first paired-end sequencing of tumors from genetically engineered mouse models of cancer to determine how faithfully these models recapitulate the landscape of somatic rearrangements found in human tumors. These were models of Trp53-mutated breast cancer, Brca1- and Brca2-associated hereditary breast cancer, and E-cadherin (Cdh1) mutated lobular breast cancer. We show that although Brca1- and Brca2-deficient mouse mammary tumors have a defect in the homologous recombination pathway, there is no apparent difference in the type or frequency of somatic rearrangements found in these cancers when compared to other mouse mammary cancers, and tumors from all genetic backgrounds showed evidence of microhomology-mediated repair and non-homologous end-joining processes. Importantly, mouse mammary tumors were found to carry fewer structural rearrangements than human mammary cancers and expressed in-frame fusion genes. Like the fusion genes found in human mammary tumors, these were not recurrent. One mouse tumor was found to contain an internal deletion of exons of the Lrp1b gene, which led to a smaller in-frame transcript. We found internal in-frame deletions in the human ortholog of this gene in a significant number (4.2%) of human cancer cell lines. Paired-end sequencing of mouse mammary tumors revealed that they display significant heterogeneity in their profiles of somatic rearrangement but, importantly, fewer rearrangements than cognate human mammary tumors, probably because these cancers have been induced by strong driver mutations engineered into the mouse genome. Both human and mouse mammary cancers carry expressed fusion genes and conserved homozygous deletions.

CDH1

Mammary tumor

10.1186/gb-2010-11-10-r100

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Citations (28)

Innovative methods for teaching molecular biology of the cell to medical students

José P. Vaqué M. Dolores Delgado Magdalena Foltman J. Méndez Ignacio Varela

Resumen del poster presentado al XL Congreso de la Sociedad Espanola de Bioquimica y Biologia Molecular (SEBBM), celebrado en Barcelona del 23 al 26 de octubre de 2017.-- Vaque, Jose P. et al.

Source

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Natural history and cell of origin of TCF3-ZNF384 and PTPN11 mutations in monozygotic twins with concordant BCP-ALL

Blood (2019)

Clara Bueno Juan Ramón Tejedor Rachael Bashford-Rogers Laura González-Silva Rafael Valdés‐Mas

PTPN11

Concordance

10.1182/blood.2019000893

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Citations (26)

Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

Genome biology (2014)

Rosalie Fisher Stuart Horswell Andrew Rowan Maximilian P Salm Elza C. de Bruin

Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma. In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.

10.1186/s13059-014-0433-z

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Citations (66)

Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets

Oncotarget (2017)

Elena Mata Antonio Díaz‐López Ana M. Martín‐Moreno Margarita Sánchez‐Beato Ignacio Varela

Defining the mutational landscape of classic Hodgkin lymphoma is still a major research goal. New targeted next-generation sequencing (NGS) techniques may identify pathogenic mechanisms and new therapeutic opportunities related to this disease. We describe the mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg (HRS) cells. Overall, the results confirm the presence of strong genomic heterogeneity. However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others. This unexpectedly high prevalence of mutations affecting the BCR pathway suggests some requirement for active BCR signaling for cHL cell viability. Additionally, incubation of a panel of cHL cellular models with selective BTK inhibitors in vitro constrains cell proliferation and causes cell death. Our results indicate new pathogenic mechanisms and therapeutic opportunities in this disease.

breakpoint cluster region

10.18632/oncotarget.22799

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Citations (40)