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.

Low expression of hexokinase-2 is associated with false-negative FDG–positron emission tomography in multiple myeloma

“…In 7 DWIBS pos PET neg cases with available copy number arrays, we neither detected a CNA involving 2p13, the locus of HK2, nor any other shared CNA that could explain this observation. Analyzing an eQTL set 14 Table S2). Future studies will have to investigate the mechanism underlying this apparent change in FDG-uptake and also the contribution of the micro-environment.…”

“…Differential gene expression was assessed as published 12,13 . An expression quantitative trait locus (eQTL) analysis was performed for polymorphisms within 1 MB of the transcription start site of Hexokinase-2 as described 14 . Copy number aberrations (CNAs) were called using HumanOmni 2.5 SNP arrays (Illumina) as described 15 .…”

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

“…CDCA7L's target CpGs did not overlap with those of CDCA7, however, they did show a similar genomic distribution and were enriched in inactive regions (Figure 4c), although enrichment at repeat regions was reduced (OR = 1.59, P > 0.05). Interestingly, previous research has shown that the risk allele of the genetic variant most highly associated with multiple myeloma (rs4487645) was associated with increased CDCA7L expression (Li et al, 2016). Our GI for CDCA7L consisted of 5 SNPs, of which one (rs17361667) was in strong LD (r 2 = 0.7) with the risk variant rs4487645.…”

Next‐generation sequencing of a family with a high penetrance of monoclonal gammopathies for the identification of candidate risk alleles

“…3 Moreover, first-degree relatives of patients with monoclonal gammopathy of undetermined significance (MGUS), the premalignant condition of MM, have an relative risk of developing MGUS of 2.6. 9,10 Recently, the availability of next-generation sequencing (NGS) techniques has opened the field to the unbiased analysis of the whole genome, and has proven successful in the study of genetic diseases. 5 At the genetic level, several genome-wide association studies (GWAS) have highlighted risk alleles for MGUS and MM, [6][7][8] but only rarely with plausible functional explanations.…”

“…5 At the genetic level, several genome-wide association studies (GWAS) have highlighted risk alleles for MGUS and MM, [6][7][8] but only rarely with plausible functional explanations. 9,10 Recently, the availability of next-generation sequencing (NGS) techniques has opened the field to the unbiased analysis of the whole genome, and has proven successful in the study of genetic diseases. 11 However, no NGS studies to date have been performed in families with a high prevalence of MGUS and MM so far.…”