Germline variants at SOHLH2 influence multiple myeloma risk.
Ontology highlight
ABSTRACT:
SUBMITTER: Duran-Lozano L
PROVIDER: S-EPMC8055668 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Genomic instability, a well-established hallmark of human cancer, is also a driving force in the natural history of multiple myeloma (MM) - a difficult to treat and in most cases fatal neoplasm of immunoglobulin producing plasma cells that reside in the hematopoietic bone marrow. Long recognized manifestations of genomic instability in myeloma at the cytogenetic level include abnormal chromosome numbers (aneuploidy) caused by trisomy of odd-numbered chromosomes; recurrent oncogene-activating chromosomal translocations that involve immunoglobulin loci; and large-scale amplifications, inversions, and insertions/deletions (indels) of genetic material. Catastrophic genetic rearrangements that either shatter and illegitimately reassemble a single chromosome (chromotripsis) or lead to disordered segmental rearrangements of multiple chromosomes (chromoplexy) also occur. Genomic instability at the nucleotide level results in base substitution mutations and small indels that affect both the coding and non-coding genome. Sometimes this generates a distinctive signature of somatic mutations that can be attributed to defects in DNA repair pathways, the DNA damage response (DDR) or aberrant activity of mutator genes including members of the APOBEC family. In addition to myeloma development and progression, genomic instability promotes acquisition of drug resistance in patients with myeloma. Here we review recent findings on the genetic predisposition to myeloma, including newly identified candidate genes suggesting linkage of germline risk and compromised genomic stability control. The role of ethnic and familial risk factors for myeloma is highlighted. We address current research gaps that concern the lack of studies on the mechanism by which germline risk alleles promote genomic instability in myeloma, including the open question whether genetic modifiers of myeloma development act in tumor cells, the tumor microenvironment (TME), or in both. We conclude with a brief proposition for future research directions, which concentrate on the biological function of myeloma risk and genetic instability alleles, the potential links between the germline genome and somatic changes in myeloma, and the need to elucidate genetic modifiers in the TME.
| S-EPMC6518313 | biostudies-literature
Project description:Multiple myeloma (MM) is a haematologic malignancy characterized by the presence of atypical plasma cells. Basigin (BSG, CD147) controls lactate export through the monocarboxylic acid transporter 1 (MCT1, SLC16A1) and supports MM survival and proliferation. Additionally, BSG is implicated in response to treatment with immunomodulatory drugs (thalidomide and its derivatives). We investigated the role of single nucleotide polymorphisms (SNPs) in the gene coding for BSG and SLC16A1 in MM. Following an in silico analysis, eight SNPs (four in BSG and four in SLC16A1) predicted to have a functional effect were selected and analyzed in 135 MM patients and 135 healthy individuals. Alleles rs4919859 C, rs8637 G, and haplotype CG were associated with worse progression-free survival (p = 0.006, p = 0.017, p = 0.002, respectively), while rs7556664 A, rs7169 T and rs1049434 A (all in linkage disequilibrium (LD), r² > 0.98) were associated with better overall survival (p = 0.021). Similar relationships were observed in thalidomide-treated patients. Moreover, rs4919859 C, rs8637 G, rs8259 A and the CG haplotype were more common in patients in stages II?III of the International Staging System (p < 0.05), while rs8259 A correlated with higher levels of β-2-microglobulin and creatinine (p < 0.05). Taken together, our results show that BSG and SLC16A1 variants affect survival, and may play an important role in MM.
| S-EPMC5977166 | biostudies-literature
Project description:Observations of inherited susceptibility to multiple myeloma have led to active research in defining predisposing genes to the disease. Here, we analysed 128 plasma cell dyscrasia patients' germline whole-exome sequencing data. Rare dominantly inherited pathogenic or likely pathogenic (P/LP) variant was found in 9.4% of the patients. Among the P/LP variants, CHEK2 (p. Thr410MetfsTer15) was the most prevalent (n = 5, 3.9%). Interestingly, P/LP variants in POT1 were identified in three patients (2.3%). Our findings broaden the spectrum of POT1-related cancers and demonstrate the importance of the germline genetic analysis in hematological malignancies.
| S-EPMC9713058 | biostudies-literature
Project description:Multiple myeloma (MM) is an incurable disease characterized by the presence of malignant plasma cells in the bone marrow that secrete specific monoclonal immunoglobulins into the blood. Obesity has been associated with the risk of developing solid and hematological cancers, but its role as a risk factor for MM needs to be further explored. Here, we evaluated whether 32 genome-wide association study (GWAS)-identified variants for obesity were associated with the risk of MM in 4189 German subjects from the German Multiple Myeloma Group (GMMG) cohort (2121 MM cases and 2068 controls) and 1293 Spanish subjects (206 MM cases and 1087 controls). Results were then validated through meta-analysis with data from the UKBiobank (554 MM cases and 402,714 controls) and FinnGen cohorts (914 MM cases and 248,695 controls). Finally, we evaluated the correlation of these single nucleotide polymorphisms (SNPs) with cQTL data, serum inflammatory proteins, steroid hormones, and absolute numbers of blood-derived cell populations (n = 520). The meta-analysis of the four European cohorts showed no effect of obesity-related variants on the risk of developing MM. We only found a very modest association of the POC5rs2112347G and ADCY3rs11676272G alleles with MM risk that did not remain significant after correction for multiple testing (per-allele OR = 1.08, p = 0.0083 and per-allele OR = 1.06, p = 0.046). No correlation between these SNPs and functional data was found, which confirms that obesity-related variants do not influence MM risk.
| S-EPMC10094344 | biostudies-literature
Project description:Multiple myeloma (MM) is a plasma-cell malignancy derived from an early precursor of the B-cell lineage characterised by bone-marrow infiltration, lytic bone lesions, and the presence of a monoclonal protein in serum and/or urine. Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B-cell development and function that is required during immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Immunomodulatory drugs, derivatives of thalidomide, are commonly used in therapy against MM. They are known to target a protein called cereblon (CRBN); however, the exact mechanism remains unknown. The present study aimed to assess the association of two (rs12203592 and rs872071) polymorphisms within the IRF4 gene and two (rs711613 and rs1045433) in the CRBN gene with MM susceptibility, progression, and response to treatment. For this purpose, 144 MM patients and 126 healthy individuals were genotyped for the IRF4 and CRBN alleles. The presence of the IRF4 (rs872071) G allele was more frequently detected in patients than healthy individuals (OR 1.78; P = 0.034), and this relationship was especially pronounced in women (OR 2.83; P = 0.012). The CRBN (rs711613) A allele-carriers were better responders to the treatment (P = 0.012), in particular to thalidomide including therapy (P = 0.023). These results underline the prognostic significance of the IRF4 and CRBN polymorphisms in patients with MM.
| S-EPMC5334380 | biostudies-literature
Project description:The metabolism of xenobiotics is regulated by phase I and II enzymes, and by transporters encoded by the absorption, distribution, metabolism, and excretion (ADME) genes. It is known that the activity of these proteins is influenced by the presence of polymorphic variants in the corresponding gene that can account for the inter-individual variability in both xenobiotic response/toxicity and disease predisposition. Exposure to pesticides and toxic substances, many of which are substrates of ADME-associated proteins, has been demonstrated to increase the risk of Multiple Myeloma (MM). To investigate the inter-individual variability of ADME genes as a risk factor for MM risk, we compared DMET Plus genotyping data from 65 MM patients with 59 CEU Hapmap controls (GPL17860).
2021-11-03 | GSE187009 | GEO
Project description:Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine.
| S-EPMC7917798 | biostudies-literature
Project description:The risk of developing multiple myeloma (MM) in first-degree relatives of affected individuals is 2 to 4 fold higher than in the general population, implying the existence of inherited susceptibility. While over 20 common, low-penetrance variants have been associated with MM risk, less is known about rare, high-penetrance germline predisposition. We aimed to identify and characterize high/moderated penetrance germline variants in MM families using whole genome sequencing. For that purpose we identified families with at least two individuals diagnosed with MM or its precursors MGUS and smoldering MM. Also, patients with solitary plasmacytoma and AL amyloidosis were enrolled. We also recruited unaffected family members, and they were screened to exclude undetected MM or its precursor stages. After whole genome sequencing of blood DNA and filtering for rare variants (minor allele frequency <0.1%) and family segregation, variants are prioritized by a range of published in silico tools and literature search. The most promising variants are subjected to experimental validation to evaluate their functional relevance. Our data will provide guidance to worldwide efforts to unravel germline predisposition in MM and validation of the proposed variants and genes.
| EGAS00001004734 | EGA
Project description:The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients by low coverage long-insert whole genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (TNFRSF17), SLAMF and MCL1. Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as CCND1 and MYC. Importantly, in 31% of patients two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis.
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Project description:Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the brain caused by reactivation of the JC virus (JCV), a polyomavirus that infects at least 60% of the population but is asymptomatic or results in benign symptoms in most people. PML occurs as a secondary disease in a variety of disorders or as a serious adverse event from immunosuppressant agents, but is mainly found in three groups: HIV-infected patients, patients with hematological malignancies, or multiple sclerosis (MS) patients on the immunosuppressant therapy natalizumab. It is severely debilitating and is deadly in ~50% HIV cases, ~90% of hematological malignancy cases, and ~24% of MS-natalizumab cases. A PML risk prediction test would have clinical utility in all at risk patient groups but would be particularly beneficial in patients considering therapy with immunosuppressant agents known to cause PML, such as natalizumab, rituximab, and others. While a JC antibody test is currently used in the clinical decision process for natalizumab, it is suboptimal because of its low specificity and requirement to periodically retest patients for seroconversion or to assess if a patient's JCV index has increased. Whereas a high specificity genetic risk prediction test comprising host genetic risk variants (i.e., germline variants occurring at higher frequency in PML patients compared to the general population) could be administered one time to provide clinicians with additional risk prediction information that is independent of JCV serostatus. Prior PML case reports support the hypothesis that PML risk is greater in patients with a genetically caused immunodeficiency disorder. To identify germline PML risk variants, we performed exome sequencing on 185 PML cases (70 in a discovery cohort and 115 in a replication cohort) and used the gnomAD variant database for interpretation. Our study yielded 19 rare variants (maximum allele frequency of 0.02 in gnomAD ethnically matched populations) that impact 17 immune function genes (10 are known to cause inborn errors of immunity). Modeling of these variants in a PML genetic risk test for MS patients considering natalizumab treatment indicates that at least a quarter of PML cases may be preventable.
| S-EPMC7094807 | biostudies-literature