ORCID Profile
0000-0002-8242-0206
Current Organisations
Royal College of Physicians
,
University of Manchester
,
Columbia University
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Publisher: Springer Science and Business Media LLC
Date: 25-12-2013
DOI: 10.1038/NATURE12873
Publisher: Springer Science and Business Media LLC
Date: 10-05-2009
DOI: 10.1038/NG.361
Publisher: Springer Science and Business Media LLC
Date: 06-07-2015
DOI: 10.1038/NCOMMS8741
Publisher: Springer Science and Business Media LLC
Date: 05-02-2015
DOI: 10.1038/NCOMMS7046
Abstract: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case–control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8 + memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.
Publisher: BMJ
Date: 28-04-2015
Publisher: Public Library of Science (PLoS)
Date: 08-11-2012
Publisher: BMJ
Date: 31-01-2012
Publisher: BMJ
Date: 04-2021
DOI: 10.1136/ANNRHEUMDIS-2021-219884
Abstract: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01 , and revealed a novel association of HLA-B*08:01 . Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.
Publisher: American Psychiatric Association Publishing
Date: 11-2017
Publisher: BMJ
Date: 18-08-2017
Publisher: Springer Science and Business Media LLC
Date: 07-06-2007
DOI: 10.1038/NATURE05911
Publisher: Elsevier BV
Date: 09-2013
Publisher: Elsevier BV
Date: 06-2017
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1965-X
Abstract: The discovery of drivers of cancer has traditionally focused on protein-coding genes 1–4 . Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of in idual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers 6,7 , raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53 , in the 3′ untranslated regions of NFKBIZ and TOB1 , focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional ex les of these drivers will be found as more cancer genomes become available.
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NATURE08979
Publisher: American Association for Cancer Research (AACR)
Date: 24-06-2021
DOI: 10.1158/1078-0432.CCR-20-4027
Abstract: The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacologic opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL. We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of IKZF1 loss of function was then validated and leveraged for combination treatment with lenalidomide. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing analyses were performed to elucidate transcriptomic and epigenetic changes underlying synergy. We identified IKZF1 knockout as the top candidate for sensitizing DLBCL cells to tazemetostat. Treating cells with tazemetostat and lenalidomide, an immunomodulatory drug that selectively degrades IKAROS and AIOLOS, phenocopied the effects of the CRISPR/Cas9 screen. The combined drug treatment triggered either cell-cycle arrest or apoptosis in a broad range of DLBCL cell lines, regardless of EZH2 mutational status. Cell-line–based xenografts also showed slower tumor growth and prolonged survival in the combination treatment group. RNA-seq analysis revealed strong upregulation of interferon signaling and antiviral immune response signatures. Gene expression of key immune response factors such as IRF7 and DDX58 were induced in cells treated with lenalidomide and tazemetostat, with a concomitant increase of H3K27 acetylation at their promoters. Furthermore, transcriptome analysis demonstrated derepression of endogenous retroviruses after combination treatment. Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.CELREP.2021.109873
Abstract: Long non-coding RNAs (lncRNAs) are increasingly recognized as functional units in cancer and powerful biomarkers however, most remain uncharacterized. Here, we analyze 5,592 prognostic lncRNAs in 9,446 cancers of 30 types using machine learning. We identify 166 lncRNAs whose expression correlates with survival and improves the accuracy of common clinical variables, molecular features, and cancer subtypes. Prognostic lncRNAs are often characterized by switch-like expression patterns. In low-grade gliomas, HOXA10-AS activation is a robust marker of poor prognosis that complements IDH1/2 mutations, as validated in another retrospective cohort, and correlates with developmental pathways in tumor transcriptomes. Loss- and gain-of-function studies in patient-derived glioma cells, organoids, and xenograft models identify HOXA10-AS as a potent onco-lncRNA that regulates cell proliferation, contact inhibition, invasion, Hippo signaling, and mitotic and neuro-developmental pathways. Our study underscores the pan-cancer potential of the non-coding transcriptome for identifying biomarkers and regulators of cancer progression.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Keren Isaev.