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

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 and Richard S. Houlston ()
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Ni Li: The Institute of Cancer Research
David C. Johnson: The Institute of Cancer Research
Niels Weinhold: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences
James B. Studd: The Institute of Cancer Research
Giulia Orlando: The Institute of Cancer Research
Fabio Mirabella: The Institute of Cancer Research
Jonathan S. Mitchell: The Institute of Cancer Research
Tobias Meissner: Avera Cancer Institute
Martin Kaiser: The Institute of Cancer Research
Hartmut Goldschmidt: University of Heidelberg
Kari Hemminki: German Cancer Research Center
Gareth J. Morgan: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences
Richard S. Houlston: The Institute of Cancer Research

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13656

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