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Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression

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 varian...

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Main Authors: Li, Lily (Author) , Johnson, David C. (Author) , Weinhold, Niels (Author) , Studd, James B. (Author) , Orlando, Giulia (Author) , Mirabella, Fabio (Author) , Mitchell, Jonathan S. (Author) , Meissner, Tobias (Author) , Kaiser, Martin (Author) , Goldschmidt, Hartmut (Author) , Hemminki, Kari (Author) , Morgan, Gareth J. (Author) , Houlston, Richard S. (Author)
Format: Article (Journal)
Language:English
Published: 24 Nov 2016
In: Nature Communications
Year: 2016, Volume: 7, Pages: 1-9
ISSN:2041-1723
DOI:10.1038/ncomms13656
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/ncomms13656
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/ncomms13656
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Author Notes:Ni Li, David C. Johnson, Niels Weinhold, James B. Studd, Giulia Orlando, Fabio Mirabella, Jonathan S. Mitchell, Tobias Meissner, Martin Kaiser, Hartmut Goldschmidt, Kari Hemminki, Gareth J. Morgan & Richard S. Houlston
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Summary: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.
Item Description:Gesehen am 04.06.2020
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/ncomms13656

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