Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

• MeSH
• B-Lymphocytes immunology   metabolism   MeSH
• Genome-Wide Association Study * MeSH
• Genetic Predisposition to Disease * MeSH
• Polymorphism, Single Nucleotide * MeSH
• Humans MeSH
• B-Cell Maturation Antigen * genetics   MeSH
• Mendelian Randomization Analysis MeSH
• Multiple Myeloma * genetics   MeSH
• Transmembrane Activator and CAML Interactor Protein genetics   MeSH
• Case-Control Studies MeSH
• Telomere genetics   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• B-Cell Maturation Antigen * MeSH
• Transmembrane Activator and CAML Interactor Protein MeSH
• TNFRSF13B protein, human MeSH Browser

• MeSH
• Genome-Wide Association Study MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Loci MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Multiple Myeloma * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH

Multiple myeloma (MM) is a plasma cell malignancy whereby a single clone of plasma cells over-propagates in the bone marrow, resulting in the increased production of monoclonal immunoglobulin. While the complex genetic architecture of MM is well characterized, much less is known about germline variants predisposing to MM. Genome-wide sequencing approaches in MM families have started to identify rare high-penetrance coding risk alleles. In addition, genome-wide association studies have discovered several common low-penetrance risk alleles, which are mainly located in the non-coding genome. Here, we further explored the genetic basis in familial MM within the non-coding genome in whole-genome sequencing data. We prioritized and characterized 150 upstream, 5' untranslated region (UTR) and 3' UTR variants from 14 MM families, including 20 top-scoring variants. These variants confirmed previously implicated biological pathways in MM development. Most importantly, protein network and pathway enrichment analyses also identified 10 genes involved in mitogen-activated protein kinase (MAPK) signaling pathways, which have previously been established as important MM pathways.

• Keywords
• MAPK pathway, familial multiple myeloma, non-coding genome, whole-genome sequencing,
• MeSH
• Genome-Wide Association Study * MeSH
• Humans MeSH
• MAP Kinase Signaling System MeSH
• Multiple Myeloma * genetics   MeSH
• Whole Genome Sequencing MeSH
• Germ-Line Mutation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

• MeSH
• Genome-Wide Association Study * methods   MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Multiple Myeloma * genetics   MeSH
• Risk Factors MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, N.I.H., Extramural MeSH

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   immunology   MeSH
• B-Lymphocytes immunology   pathology   MeSH
• Chromatin chemistry   immunology   MeSH
• Chromosomal Proteins, Non-Histone genetics   immunology   MeSH
• Genetic Predisposition to Disease * MeSH
• Risk Assessment MeSH
• DNA, Intergenic genetics   immunology   MeSH
• Humans MeSH
• Quantitative Trait Loci MeSH
• Multiple Myeloma drug therapy   genetics   immunology   pathology   MeSH
• Neoplasm Proteins genetics   immunology   MeSH
• Plasma Cells immunology   pathology   MeSH
• Polymorphism, Genetic MeSH
• Primary Cell Culture MeSH
• Cell Cycle Proteins genetics   immunology   MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Repressor Proteins genetics   immunology   MeSH
• Base Sequence MeSH
• Transcriptional Elongation Factors genetics   immunology   MeSH
• Inheritance Patterns MeSH
• Guanine Nucleotide Exchange Factors genetics   immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• CDCA7L protein, human MeSH Browser
• CEP120 protein, human MeSH Browser
• Chromatin MeSH
• Chromosomal Proteins, Non-Histone MeSH
• ELL2 protein, human MeSH Browser
• DNA, Intergenic MeSH
• Neoplasm Proteins MeSH
• PREX1 protein, human MeSH Browser
• Cell Cycle Proteins MeSH
• Repressor Proteins MeSH
• SMARCD3 protein, human MeSH Browser
• Transcriptional Elongation Factors MeSH
• Guanine Nucleotide Exchange Factors MeSH
• WAC protein, human MeSH Browser

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.

• Keywords
• clinical presentation, plasma cell disease, risks factors, survival, treatment,
• MeSH
• Cyclin D1 genetics   MeSH
• Exosome Multienzyme Ribonuclease Complex genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Histone Demethylases genetics   MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Survival Rate MeSH
• Multiple Myeloma diagnosis   epidemiology   genetics   therapy   MeSH
• Mutation MeSH
• Biomarkers, Tumor genetics   MeSH
• Plasma Cells immunology   pathology   MeSH
• Repressor Proteins genetics   MeSH
• Risk Factors MeSH
• Transcriptional Elongation Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• CCND1 protein, human MeSH Browser
• CDCA7L protein, human MeSH Browser
• Cyclin D1 MeSH
• DIS3 protein, human MeSH Browser
• ELL2 protein, human MeSH Browser
• Exosome Multienzyme Ribonuclease Complex MeSH
• Histone Demethylases MeSH
• KDM1A protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• Repressor Proteins MeSH
• Transcriptional Elongation Factors MeSH

Transcription factor Growth Factor Independence 1 (GFI1) regulates the expression of genes important for survival, proliferation and differentiation of hematopoietic cells. A single nucleotide polymorphism (SNP) variant of GFI1 (GFI1-36N: serine replaced by asparagine at position 36), has a prevalence of 5-7% among healthy Caucasians and 10-15% in patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) predisposing GFI-36N carriers to these diseases. Since GFI1 is implicated in B cell maturation and plasma cell (PC) development, we examined its prevalence in patients with multiple myeloma (MM), a haematological malignancy characterized by expansion of clonal PCs. Strikingly, as in MDS and AML, we found that the GFI1-36N had a higher prevalence among MM patients compared to the controls. In subgroup analyses, GFI1-36N correlates to a shorter overall survival of MM patients characterized by the presence of t(4;14) translocation and gain of 1q21 (≤3 copies). MM patients carrying gain of 1q21 (≥3 copies) demonstrated poor progression free survival. Furthermore, gene expression analysis implicated a role for GFI1-36N in epigenetic regulation and metabolism, potentially promoting the initiation and progression of MM.

• Keywords
• Gfi1, SNP variant, multiple myeloma, prevalance, prognosis,
• Publication type
• Journal Article MeSH

• MeSH
• Genetic Predisposition to Disease MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Multiple Myeloma genetics   MeSH
• Pedigree MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH