title: Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression.
abstract: Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10-25), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10-36), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter. We show that suppression of CDCA7L limits MM proliferation through apoptosis, and increased CDCA7L expression is associated with adverse patient survival. These findings implicate IRF4-mediated CDCA7L expression in MM biology and indicate how germline variation might confer susceptibility to MM.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK.|Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Ni
authors.initials: N
authors.lastname: Li
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: David C
authors.identifier: http://orcid.org/0000-0003-0887-3343
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.|Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: James B
authors.identifier: http://orcid.org/0000-0002-7157-754X
authors.initials: JB
authors.lastname: Studd
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Orlando
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Fabio
authors.identifier: http://orcid.org/0000-0003-3785-6868
authors.initials: F
authors.lastname: Mirabella
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Mitchell
authors.affiliation: Department of Molecular and Experimental Medicine, Avera Cancer Institute, La Jolla, California 92037, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Meissner
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany.|National Centre of Tumor Diseases, 69120 Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, SE-205 02 Malmo, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK.|Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000483:Alleles; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D040641:Quantitative Trait Loci; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D000099218:Interferon Regulatory Factor-4; C513450:CDCA7L protein, human