Abstract:The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1–5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however iden… Show more
“…By referencing germline whole-genome sequencing (WGS) data on 640 MM patients analyzed as part of the CoMMpass Study ( Craig et al., 2013 ), we were able to confirm that the imputation captured >90% of sequence variation (minor allele frequency [MAF] > 0.05) within the linkage disequilibrium (LD) region encompassing rs11372862 (i.e., pairwise r 2 ≥ 0.1) ( Table S1 ). By analyzing the germline exomes of 513 MM case subjects from the UK Medical Research Council (MRC) MyIX and MyXI clinical trials and 1,569 UK control subjects from the UK 1958 Birth Cohort ( Scales et al., 2017 ), we excluded the possibility that the 5q15 association signal is a consequence of LD with a rare disease-causing coding variant ( Table S2 ). Figure 1 Regional Plots of Association Results of the 5q15 Locus (A and B) The region of association maps to a ∼40 kb haplotype block within ELL2 .…”
SummaryMultiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.
“…By referencing germline whole-genome sequencing (WGS) data on 640 MM patients analyzed as part of the CoMMpass Study ( Craig et al., 2013 ), we were able to confirm that the imputation captured >90% of sequence variation (minor allele frequency [MAF] > 0.05) within the linkage disequilibrium (LD) region encompassing rs11372862 (i.e., pairwise r 2 ≥ 0.1) ( Table S1 ). By analyzing the germline exomes of 513 MM case subjects from the UK Medical Research Council (MRC) MyIX and MyXI clinical trials and 1,569 UK control subjects from the UK 1958 Birth Cohort ( Scales et al., 2017 ), we excluded the possibility that the 5q15 association signal is a consequence of LD with a rare disease-causing coding variant ( Table S2 ). Figure 1 Regional Plots of Association Results of the 5q15 Locus (A and B) The region of association maps to a ∼40 kb haplotype block within ELL2 .…”
SummaryMultiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.
“…The results showed that after silencing KIF18A, cell proliferation, cell invasion and migration decreased in minimally invasive HepG2 cells and highly invasive SMMC-7721 cells. For these changes, the relevant literature suggests that the KIF18A gene causes dysregulation of cell mitosis control and promotes cell division [ 15 ]; however, the mechanism remains uncertain. In one of the Przybyl studies, regulation of impaired mitosis in the early stage of the tumour can cause synsa [ 16 ].…”
BackgroundKIF18A is associated with a variety of tumours; however, the specific mechanism of action of KIF18A in hepatocellular carcinoma (HCC) remains unclear. In this study, in vitro and in vivo experiments were performed with the aim of exploring the potential function and molecular mechanism of kinesin KIF18A in the occurrence and development of HCC.MethodsWe detected the expression of KIF18A in tumour and adjacent tissues as well as cell proliferation, cell invasion and migration in hepatoma cells after silencing KIF18A. KIF18A-silenced hepatoma cells were subcutaneously injected into nude mice to verify the tumorigenicity of KIF18A. We also detected the expression of signal pathway-related proteins in hepatoma cells after KIF18A knockdown with the aim of exploring the association between KIF18A and related signalling pathways.ResultsThe level of KIF18A protein was higher in liver cancer tissues than adjacent tissues. After silencing KIF18A in SMMC-7721 and HepG2 cells, cell growth was obviously inhibited; the migration and invasion abilities were significantly decreased and the in vivo tumour weight was decreased compared to the control group (0.201 ± 0.088 g vs 0.476 ± 0.126 g, p = 0.009). The expression of cell cycle-related protein (cyclin B1), invasion and metastasis-related proteins (MMP-7 and MMP-9) and Akt-related proteins in hepatoma cells was also decreased after knocking down KIF18A.ConclusionsKIF18A may promote proliferation, invasion and metastasis of HCC cells by promoting the cell cycle signalling pathway as well as the Akt and MMP-7/MMP-9-related signalling pathways and may serve as a new target for the diagnosis and treatment of HCC.
“…Scales et al recently reported an MM exome mutation burden test study in 513 United Kingdom northern EA MM cases from two clinical trials (48). While no individual gene reached genomewide significance in this study, the authors nominated KIF18A as a promising MM predisposition candidate.…”
Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation. KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. .
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