Multiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression.
Date
2016-11-24Author
Li, N
Johnson, DC
Weinhold, N
Studd, JB
Orlando, G
Mirabella, F
Mitchell, JS
Meissner, T
Kaiser, M
Goldschmidt, H
Hemminki, K
Morgan, GJ
Houlston, RS
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Humans
Multiple Myeloma
Genetic Predisposition to Disease
Proto-Oncogene Proteins c-myc
Repressor Proteins
Apoptosis
Gene Expression Regulation, Neoplastic
Protein Binding
Polymorphism, Single Nucleotide
Alleles
Quantitative Trait Loci
Interferon Regulatory Factors
Enhancer Elements, Genetic
Promoter Regions, Genetic
Research team
Cancer Genomics
Molecular & Population Genetics
Myeloma Group
Language
eng
Date accepted
2016-10-19
License start date
2016-11-24
Citation
Nature communications, 2016, 7 pp. 13656 - ?
Publisher
NATURE PUBLISHING GROUP