Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics

Helen E. Speedy, Renée Beekman, Vicente Chapaprieta, Giulia Orlando, Philip J. Law, David Martín-García, Jesús Gutiérrez-Abril, Daniel Catovsky, Sílvia Beà, Guillem Clot, Montserrat Puiggròs, David Torrents, Xose S. Puente, James M. Allan, Carlos López-Otín, Elias Campo, Richard S. Houlston () and José I. Martín-Subero ()
Additional contact information
Helen E. Speedy: Institute of Cancer Research
Renée Beekman: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Vicente Chapaprieta: Universitat de Barcelona
Giulia Orlando: Institute of Cancer Research
Philip J. Law: Institute of Cancer Research
David Martín-García: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Jesús Gutiérrez-Abril: Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo
Daniel Catovsky: Institute of Cancer Research
Sílvia Beà: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Guillem Clot: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Montserrat Puiggròs: Universitat de Barcelona
David Torrents: Universitat de Barcelona
Xose S. Puente: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
James M. Allan: Newcastle University
Carlos López-Otín: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Elias Campo: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Richard S. Houlston: Institute of Cancer Research
José I. Martín-Subero: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.

Date: 2019
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DOI: 10.1038/s41467-019-11582-2

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