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  • Morgan, Gareth J  (32)
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  • 1
    In: British Journal of Haematology, August 2013, Vol.162(3), pp.348-359
    Description: Multiple myeloma () is a heterogeneous disease. International Staging System/fluorescence hybridization (/)‐based model and gene expression profiles () are effective approaches to define clinical outcome, although yet to be improved. The discovery of a class of small non‐coding s (micro s, mis) has revealed a new level of biological complexity underlying the regulation of gene expression. In this work, 163 presenting samples from patients were analysed by global mi profiling, and distinct mi expression characteristics in molecular subgroups with prognostic relevance (4p16, and 11q13 translocations) were identified. Furthermore we developed an “outcome classifier”, based on the expression of two mis (17 and 886‐5p), which is able to stratify patients into three risk groups (median 19·4, 40·6 and 65·3 months, =0·001). The mi‐based classifier significantly improved the predictive power of the / approach (=0·0004), and was independent of ‐derived prognostic signatures (〈0·002). Through integrative genomics analysis, we outlined the potential biological relevance of the mis included in the classifier and their putative roles in regulating a large number of genes involved in biology. This is the first report showing that mis can be built into molecular diagnostic strategies for risk stratification in .
    Keywords: Myeloma ; Micro ; Risk Stratification ; Outcome Classifier ; Genomic Profiling
    ISSN: 0007-1048
    E-ISSN: 1365-2141
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  • 2
    Language: English
    In: Blood, 05 October 2017, Vol.130(14), pp.1639-1643
    Description: Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in nonintensively treated patients, which is consistent with the reduced therapeutic efficacy of microenvironment-modulating IMiDs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcomes and personalizing therapy.
    Keywords: Gene Frequency ; Mutation ; Immunologic Factors -- Therapeutic Use ; Multiple Myeloma -- Drug Therapy ; Thalidomide -- Analogs & Derivatives
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 3
    Language: English
    In: Blood, 06 December 2018, Vol.132(23), pp.2465-2469
    Description: Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; = .01). Clonal, but not subclonal, deletions were associated with clinical markers of advanced disease, specifically lower platelet counts ( 〈 .001) and increased lactate dehydrogenase ( 〈 .001), as well as a higher frequency of features indicative of genomic instability, del(13q) ( = .002) or del(1p) ( = .006). Biallelic loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.
    Keywords: Gene Deletion ; Gene Dosage ; Genomic Instability ; Multiple Myeloma -- Genetics ; Tumor Suppressor Protein P53 -- Genetics
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 4
    Language: English
    In: Blood, 27 December 2018, Vol.132(26), pp.2775-2777
    Keywords: Mutation ; Immunoglobulin Light-Chain Amyloidosis -- Genetics ; Plasma Cells -- Immunology
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 December 2016, Vol.22(23), pp.5783-5794
    Description: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease. In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers. Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783-94. ©2016 AACR.
    Keywords: Multiple Myeloma -- Genetics ; Mutation -- Genetics
    ISSN: 1078-0432
    E-ISSN: 15573265
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    In: Nature Genetics, 2013, Vol.45(5), p.522
    Description: A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyo-type. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G〉A polymorphism (P = 7.96 x [10.sup.-11]). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation. RAF GG GA AA RAF GG GA AA
    Keywords: Multiple Myeloma -- Risk Factors ; Multiple Myeloma -- Genetic Aspects ; Multiple Myeloma -- Research ; Single Nucleotide Polymorphisms -- Research ; Immunoglobulins -- Health Aspects ; Immunoglobulins -- Genetic Aspects ; Immunoglobulins -- Research;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 7
    Language: English
    In: Blood, 25 April 2013, Vol.121(17), pp.3413-9
    Description: Translocations in myeloma are thought to occur solely in mature B cells in the germinal center through class switch recombination (CSR). We used a targeted captured technique followed by massively parallel sequencing to determine the exact breakpoints in both the immunoglobulin heavy chain (IGH) locus and the partner chromosome in 61 presentation multiple myeloma samples. The majority of samples (62%) have a breakpoint within the switch regions upstream of the IGH constant genes and are generated through CSR in a mature B cell. However, the proportion of CSR translocations is not consistent between cytogenetic subgroups. We find that 100% of t(4;14) are CSR-mediated; however, 21% of t(11;14) and 25% of t(14;20) are generated through DH-JH recombination activation gene-mediated mechanisms, indicating they occur earlier in B-cell development at the pro-B-cell stage in the bone marrow. These 2 groups also generate translocations through receptor revision, as determined by the breakpoints and mutation status of the segments used in 10% and 50% of t(11;14) and t(14;20) samples, respectively. The study indicates that in a significant number of cases the translocation-based etiological events underlying myeloma may arise at the pro-B-cell hematological progenitor cell level, much earlier in B-cell development than was previously thought.
    Keywords: Chromosome Breakage ; Germinal Center -- Pathology ; Immunoglobulin Heavy Chains -- Genetics ; Multiple Myeloma -- Genetics ; Precursor Cells, B-Lymphoid -- Pathology ; Translocation, Genetic -- Genetics
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 8
    Language: English
    In: Nature communications, 08 January 2016, Vol.7, pp.10290
    Description: Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10(-9)). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors.
    Keywords: Chromosomes, Human, Pair 6 -- Genetics ; Multiple Myeloma -- Genetics
    E-ISSN: 2041-1723
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  • 9
    Language: English
    In: Leukemia, February 2014, Vol.28(2), pp.384-390
    Description: The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia (PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.
    Keywords: Cell Transformation, Neoplastic -- Genetics ; Multiple Myeloma -- Genetics
    ISSN: 08876924
    E-ISSN: 1476-5551
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  • 10
    In: Scientific Reports, 2015, Vol.5
    Description: A sizeable fraction of multiple myeloma (MM) is expected to be explained by heritable factors. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing MM risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to 2,282 cases and 5,197 controls individuals to estimate the heritability of MM. We estimated that the heritability explained by known common MM risk SNPs identified in GWAS was 2.9% (± 2.4%), whereas the heritability explained by all common SNPs was 15.2% (± 2.8%). Comparing the heritability explained by the common variants with that from family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In summary, our results suggest that known MM SNPs only explain a small proportion of the heritability and more common SNPs remain to be identified.
    Keywords: Genetic Predisposition to Disease ; Genome, Human ; Polymorphism, Single Nucleotide ; Quantitative Trait, Heritable ; Multiple Myeloma -- Genetics;
    ISSN: 20452322
    E-ISSN: 20452322
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