The 7p15.3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells

Weinhold, Niels; Meißner, Tobias; Johnson, David C.; Seckinger, Anja; Moreaux, Jérôme; Försti, Asta; Chen, Bowang; Nickel, Jolanta; Chubb, Daniel; Rawstron, Andy C.; Doughty, Chi; Dahir, Nasrin; Begum, Dil; Young, Kwee; Walker, Brian A.; Hoffmann, Per; Nöthen, M. M.; Davies, Faith E.; Klein, Bernard; Goldschmidt, Hartmut; Morgan, Gareth J.; Houlston, Richard S.; Hose, Dirk; Hemminki, Kari

doi:10.3324/haematol.2014.118786

Cited by 30 publications

(36 citation statements)

References 15 publications

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“…Besides confirming that the association of rs4487645 with CDCA7L was the strongest 7p15.3 eQTL ( P =1.95 × 10 −36 ; linear regression followed by fixed-effects meta-analysis; Supplementary Table 1 and Supplementary Fig. 1), conditional analysis provided no evidence for additional independent signals10.…”

Section: Resultsmentioning

confidence: 90%

“…Previously, we demonstrated an expression quantitative trait locus (eQTL) signal between rs4487645 and CDCA7L (ref. 10), with the risk allele associated with increased expression of CDCA7L . To further substantiate this eQTL, we analysed mRNA expression data on CD138-purified plasma cells from 1,449 MM cases from three independent series.…”

Section: Resultsmentioning

confidence: 99%

“…eQTL analyses were performed for genes within 1 MB of rs4487645 for CD138-purified plasma cells from 183 MRC Myeloma IX trial patients (GSE21349), 658 Heidelberg patients (E-MTAB-2299) and 608 US patients (GSE2658, GSE31161) using Affymetrix Human Genome U133 2.0 Plus Array10 (Supplementary Table 3). Briefly, German, UK and US data were pre-processed separately, followed by analysis using a Bayesian approach to probabilistic estimation of expression residuals to infer broad variance components, accounting for hidden determinants influencing global expression (for example, copy number, translocation status and batch effects).…”

Section: Methodsmentioning

confidence: 99%

“…We pooled data from each of the three studies under a fixed-effects model, controlling for false discovery rate (FDR) and calling significant associations with FDR≤0.05. Conditional analysis was performed as described previously10.…”

Section: Methodsmentioning

confidence: 99%

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

Johnson

Weinhold

et al. 2016

Nat Commun

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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.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Johnson

Weinhold

et al. 2016

Nat Commun

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“…This situation could be explained by remote regulation among related genes, and is common in many other studies [32][33][34]. For example, Weinhold et al [32] conducted eQTL analysis and found that at 7p15.3 the strongest association with multiple myeloma risk was for rs4487645, residing within the DNAH11 gene, which was associated with allele-specific regulation of the CDCA7L gene (near the DNAH11 gene). In our study, CARS, together with the NAP1L4, PHLDA2, SLC22A18, and CARS-AS1 genes, is located at or near the important tumor-suppressor gene region (11p15.5).…”

Section: Discussionmentioning

confidence: 92%

Polymorphisms in CARS are associated with gastric cancer risk: a two-stage case–control study in the Chinese population

Tian

Xiao

et al. 2017

Gastric Cancer

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Background The cysteinyl transfer RNA synthetase gene (CARS) is located on chromosome band 11p15.5, which is an important tumor-suppressor gene region. Mutations in CARS have been identified in many kinds of cancers; however, evidence for a relationship between genetic variants in CARS and gastric cancer at the population level is still lacking. Thus, we explored the association of variants in CARS with gastric cancer using a two-stage casecontrol strategy in Chinese. Methods We undertook a two-stage case-control study to investigate the association between polymorphisms in CARS and risk of gastric cancer with use of an Illumina Infinium Ò BeadChip and an ABI 7900 system. Results Four single nucleotide polymorphisms (SNPs) were significantly associated with gastric cancer risk in both the discovery stage and the validation stage after adjustment for age and sex. In addition, the combined results of the two stages showed these SNPs were related to gastric cancer risk (P false discovery rate B 0.001 for rs384,490, rs729662, rs2071101, and rs7394702). In silico analyses revealed that rs384490 and rs7394702 could affect transcription factor response elements or DNA methylation of CARS, and rs729662 was associated with the prognosis of gastric cancer. Additionally, expression quantitative trait loci analysis showed rs384490 and rs729662 might alter expression of CARS-related genes. Conclusions The potential functional SNPs in CARS might influence the biological functions of CARS or CARS-related genes and ultimately modify the occurrence and development of gastric cancer in Chinese. Further large-scale population-based studies or biological functional assays are warranted to validate our findings.

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Epidemiology, genetics and treatment of multiple myeloma and precursor diseases

Hemminki

Försti

Houlston

et al. 2021

Intl Journal of Cancer

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Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapies. Areas of unmet need include the management of patients with high-risk MM, those with reduced performance status and those refractory to standard therapies. Ongoing research into the biology and early detection of MM as well as the development of novel therapies, such as immunotherapies, has the potential to influence MM practice in the future.

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The 7p15.3 (rs4487645) association for multiple myeloma shows strong allele-specific regulation of the MYC-interacting gene CDCA7L in malignant plasma cells

Cited by 30 publications

References 15 publications

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

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

Polymorphisms in CARS are associated with gastric cancer risk: a two-stage case–control study in the Chinese population

Epidemiology, genetics and treatment of multiple myeloma and precursor diseases

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