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Myeloma genomics

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https://www.readbyqxmd.com/read/29760015/novel-genomic-findings-in-multiple-myeloma-identified-through-routine-diagnostic-sequencing
#1
Georgina L Ryland, Kate Jones, Melody Chin, John Markham, Elle Aydogan, Yamuna Kankanige, Marisa Caruso, Jerick Guinto, Michael Dickinson, H Miles Prince, Kwee Yong, Piers Blombery
AIMS: Multiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre. METHODS: A cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline...
May 14, 2018: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29759151/circulating-tumour-dna-for-detecting-minimal-residual-disease-in-multiple-myeloma
#2
REVIEW
Trevor J Pugh
Circulating tumor DNA faithfully recapitulates somatic mutations detected in bone marrow aspirates from patients with newly diagnosed or relapsed or recurrent myeloma. Extending these methods to enable detection of minimal residual disease will require increased sensitivity and breadth of genomic assays to maximize information content from small quantities of cell-free DNA; as well as definition of a clinically meaningful ctDNA concentration in comparison with conventional bone marrow cell-count thresholds...
January 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29749395/genomic-discovery-and-clonal-tracking-in-multiple-myeloma-by-cell-free-dna-sequencing
#3
Guangwu Guo, Noopur S Raje, Charles Seifer, Jake Kloeber, Randi Isenhart, Gavin Ha, Andrew J Yee, Elizabeth K O'Donnell, Yu-Tzu Tai, Paul G Richardson, Giada Bianchi, Jacob P Laubach, Diane Warren, Erica Gemme, Jordan Voisine, Julia Frede, Antonis Kokkalis, Huiyoung Yun, Valeriya Dimitrova, Tushara Vijaykumar, Matthew Meyerson, Nikhil C Munshi, Kenneth C Anderson, Birgit Knoechel, Jens G Lohr
No abstract text is available yet for this article.
March 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29747599/predicting-multi-level-drug-response-with-gene-expression-profile-in-multiple-myeloma-using-hierarchical-ordinal-regression
#4
Xinyan Zhang, Bingzong Li, Huiying Han, Sha Song, Hongxia Xu, Yating Hong, Nengjun Yi, Wenzhuo Zhuang
BACKGROUND: Multiple myeloma (MM), like other cancers, is caused by the accumulation of genetic abnormalities. Heterogeneity exists in the patients' response to treatments, for example, bortezomib. This urges efforts to identify biomarkers from numerous molecular features and build predictive models for identifying patients that can benefit from a certain treatment scheme. However, previous studies treated the multi-level ordinal drug response as a binary response where only responsive and non-responsive groups are considered...
May 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29721253/neurofibromatosis-type-i-and-multiple-myeloma-coexistence-a-possible-link
#5
Fabrizio Accardi, Valentina Marchica, Cristina Mancini, Elena Maredi, Costantina Racano, Laura Notarfranchi, Davide Martorana, Paola Storti, Eugenia Martella, Benedetta Dalla Palma, Luisa Craviotto, Massimo De Filippo, Antonio Percesepe, Franco Aversa, Nicola Giuliani
The association between Neurofibromatosis type I (NF1) and multiple myeloma (MM), a plasma cell, dyscrasia is very rare. Here we put to the attention of the scientific community two new cases. The first one is a patient with active MM whereas the second with smoldering MM. Both patients present typical features of NF1 but skeletal alterations were present only in the second case including dysplasia, marked scoliosis and osteoporosis. MM osteolytic lesions were absent in both patients. In addition to the clinical diagnosis of NF1, a molecular testing for NF1 gene mutations has been performed finding that patient one was heterozygous for the c...
March 2, 2018: Hematology Reports
https://www.readbyqxmd.com/read/29703982/whole-exome-sequencing-of-cell-free-dna-and-circulating-tumor-cells-in-multiple-myeloma
#6
S Manier, J Park, M Capelletti, M Bustoros, S S Freeman, G Ha, J Rhoades, C J Liu, D Huynh, S C Reed, G Gydush, K Z Salem, D Rotem, C Freymond, A Yosef, A Perilla-Glen, L Garderet, E M Van Allen, S Kumar, J C Love, G Getz, V A Adalsteinsson, I M Ghobrial
Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole-genome sequencing, we find both tumor fractions correlate with disease progression...
April 27, 2018: Nature Communications
https://www.readbyqxmd.com/read/29703720/from-mgus-to-multiple-myeloma-a-paradigm-for-clonal-evolution-of-premalignant-cells
#7
REVIEW
Niels van Nieuwenhuijzen, Ingrid Spaan, Reinier Raymakers, Victor Peperzak
Multiple myeloma (MM) is a treatable, but incurable, malignancy of plasma cells (PC) in the bone marrow (BM). It represents the final stage in a continuum of PC dyscrasias and is consistently preceded by a premalignant phase termed monoclonal gammopathy of undetermined significance (MGUS). The existence of this well-defined premalignant phase provides the opportunity to study clonal evolution of a premalignant condition into overt cancer. Unraveling the mechanisms of malignant transformation of PC could enable early identification of MGUS patients at high risk of progression and may point to novel therapeutic targets, thereby possibly delaying or preventing malignant transformation...
April 27, 2018: Cancer Research
https://www.readbyqxmd.com/read/29700321/a-compendium-of-long-non-coding-rnas-transcriptional-fingerprint-in-multiple-myeloma
#8
Domenica Ronchetti, Luca Agnelli, Alessandro Pietrelli, Katia Todoerti, Martina Manzoni, Elisa Taiana, Antonino Neri
Multiple myeloma (MM) is a clonal proliferation of bone marrow plasma cells characterized by highly heterogeneous genetic background and clinical course, whose pathogenesis remains largely unknown. Long ncRNAs (lncRNAs) are a large class of non-protein-coding RNA, involved in many physiological cellular and genomic processes as well as in carcinogenesis and tumor evolution. Although still in its infancy, the role of lncRNAs in MM is progressively expanding. Besides studies on selected candidates, lncRNAs expression at genome-wide transcriptome level is confined to microarray technologies, thus investigating a limited collection of transcripts...
April 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29695719/the-multiple-myeloma-risk-allele-at-5q15-lowers-ell2-expression-and-increases-ribosomal-gene-expression
#9
Mina Ali, Ram Ajore, Anna-Karin Wihlborg, Abhishek Niroula, Bhairavi Swaminathan, Ellinor Johnsson, Owen W Stephens, Gareth Morgan, Tobias Meissner, Ingemar Turesson, Hartmut Goldschmidt, Ulf-Henrik Mellqvist, Urban Gullberg, Markus Hansson, Kari Hemminki, Hareth Nahi, Anders Waage, Niels Weinhold, Björn Nilsson
Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (Pcombined  = 2.5 × 10-27 ; βcombined  = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines...
April 25, 2018: Nature Communications
https://www.readbyqxmd.com/read/29669929/antigen-mediated-regulation-in-monoclonal-gammopathies-and-myeloma
#10
Shiny Nair, Joel Sng, Chandra Sekhar Boddupalli, Anja Seckinger, Marta Chesi, Mariateresa Fulciniti, Lin Zhang, Navin Rauniyar, Michael Lopez, Natalia Neparidze, Terri Parker, Nikhil C Munshi, Rachael Sexton, Bart Barlogie, Robert Orlowski, Leif Bergsagel, Dirk Hose, Richard A Flavell, Pramod K Mistry, Eric Meffre, Madhav V Dhodapkar
A role for antigen-driven stimulation has been proposed in the pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) based largely on the binding properties of monoclonal Ig. However, insights into antigen binding to clonal B cell receptors and in vivo responsiveness of the malignant clone to antigen-mediated stimulation are needed to understand the role of antigenic stimulation in tumor growth. Lysolipid-reactive clonal Ig were detected in Gaucher disease (GD) and some sporadic gammopathies...
April 19, 2018: JCI Insight
https://www.readbyqxmd.com/read/29603773/treatment-patterns-and-clinical-outcomes-in-high-risk-newly-diagnosed-multiple-myeloma-patients-carrying-the-17p-deletion-an-observational-multi-center-retrospective-study
#11
Yael C Cohen, Avi Saranga, Moshe E Gatt, Noa Lavi, Chezi Ganzel, Hila Magen, Irit Avivi, Tamar Tadmor, Celia Suriu, Osnat Jarchowsky Dolberg, Amitai Papushado, Svetlana Trestman, Ron Ram
Del17p is a genomic imbalance occurring in ∼7-10% of myeloma at diagnosis (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008-1/2016 proven to carry 17p deletion by means of FISH were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance...
March 31, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29594489/host-genetic-susceptibility-to-clostridium-difficile-infections-in-patients-undergoing-autologous-stem-cell-transplantation-a-genome-wide-association-study
#12
Senu Apewokin, Jeannette Y Lee, Julia A Goodwin, Kent D McKelvey, Owen W Stephens, Daohong Zhou, Elizabeth Ann Coleman
BACKGROUND: Clostridium difficile infection (CDI) is the most common hospital-acquired infection. Unfortunately, genes that identify CDI-susceptible patients have not been well described. We performed a genome-wide association study (GWAS) to determine genetic variants associated with the development of CDI. METHODS: A cohort study of Caucasian patients undergoing autologous stem cell transplantation for multiple myeloma was performed. Patients were genotyped using Illumina® Whole Genome Genotyping Infinium chemistry...
March 28, 2018: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
https://www.readbyqxmd.com/read/29563506/a-multiple-myeloma-specific-capture-sequencing-platform-discovers-novel-translocations-and-frequent-risk-associated-point-mutations-in-igll5
#13
Brian S White, Irena Lanc, Julie O'Neal, Harshath Gupta, Robert S Fulton, Heather Schmidt, Catrina Fronick, Edward A Belter, Mark Fiala, Justin King, Greg J Ahmann, Mary DeRome, Elaine R Mardis, Ravi Vij, John F DiPersio, Joan Levy, Daniel Auclair, Michael H Tomasson
Multiple myeloma (MM) is a disease of copy number variants (CNVs), chromosomal translocations, and single-nucleotide variants (SNVs). To enable integrative studies across these diverse mutation types, we developed a capture-based sequencing platform to detect their occurrence in 465 genes altered in MM and used it to sequence 95 primary tumor-normal pairs to a mean depth of 104×. We detected cases of hyperdiploidy (23%), deletions of 1p (8%), 6q (21%), 8p (17%), 14q (16%), 16q (22%), and 17p (4%), and amplification of 1q (19%)...
March 21, 2018: Blood Cancer Journal
https://www.readbyqxmd.com/read/29542132/how-do-we-manufacture-clinical-grade-interleukin-15-stimulated-natural-killer-cell-products-for-cancer-treatment
#14
Lucía Fernández, Alejandra Leivas, Jaime Valentín, Adela Escudero, Dolores Corral, Raquel de Paz, Maria Vela, David Bueno, Rebeca Rodríguez, Juan Manuel Torres, Mariana Díaz-Almirón, Eduardo López-Collazo, Joaquin Martinez-Lopez, Antonio Pérez-Martínez
BACKGROUND: Cancer immunotherapy involving natural killer (NK) cells has gained interest. Here we report two methods to obtain interleukin (IL)-15-activated NK cells for clinical use. STUDY DESIGN AND METHODS: IL-15-activated NK cell products were obtained after 1) enrichment from healthy haploidentical donors' peripheral blood mononuclear cells (PBMNCs) collected by nonmobilized apheresis by a two-step magnetic procedure, depletion of CD3+ cells followed by selection of CD56+ cells and ex vivo overnight stimulation with IL-15 (NKIL15); and 2) expansion using the K562-mb15-41BBL cell line (NKAE), from autologous PBMNCs from patients with multiple myeloma or expansion from healthy haploidentical PBMNCs obtained from whole blood using the same previous cell line...
March 14, 2018: Transfusion
https://www.readbyqxmd.com/read/29506935/prognostic-biomarkers-in-the-progression-from-mgus-to-multiple-myeloma-a-systematic-review
#15
REVIEW
Charlotte Cosemans, Bénedith Oben, Ingrid Arijs, Annick Daniëls, Jeroen Declercq, Kimberly Vanhees, Guy Froyen, Brigitte Maes, Jeroen Mebis, Jean-Luc Rummens
Multiple myeloma (MM), characterized by malignant plasma cells in the bone marrow, is consistently preceded by asymptomatic premalignant stage monoclonal gammopathy of undetermined significance (MGUS). These MGUS patients have an annual risk of 1% to progress to MM. Clinical, imaging, and genomic (genetic and epigenetic) factors were identified, whose presence increased the risk of progression from MGUS to MM. In this systematic review we summarize the currently identified clinical, imaging, and genomic biomarkers suggested to increase the progression risk or shown to be differentially expressed/present between both cohorts of patients...
April 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29467487/loss-of-heterozygosity-as-a-marker-of-homologous-repair-deficiency-in-multiple-myeloma-a-role-for-parp-inhibition
#16
Charlotte Pawlyn, Andrea Loehr, Cody Ashby, Ruslana Tytarenko, Shayu Deshpande, James Sun, Kyle Fedorchak, Tariq Mughal, Faith E Davies, Brian A Walker, Gareth J Morgan
PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29463311/myeloid-transformation-of-plasma-cell-myeloma-molecular-evidence-of-clonal-evolution-revealed-by-next-generation-sequencing
#17
Jonathon H Gralewski, Ginell R Post, Frits van Rhee, Youzhong Yuan
BACKGROUND: Plasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes with molecular heterogeneity. Although therapy-related myeloid neoplasms are common in plasma cell myeloma patients after chemotherapy, transdifferentiation of plasma cell myeloma into myeloid neoplasms has not been reported in literature. Here we report a very rare case of myeloid neoplasm transformed from plasma cell myeloma. CASE PRESENTATION: A 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant...
February 20, 2018: Diagnostic Pathology
https://www.readbyqxmd.com/read/29414394/importin-%C3%AE-and-exportin-5-are-strong-biomarkers-of-productive-reoviral-infection-of-cancer-cells
#18
Gerard Nuovo, Hue Tran, Andres Gutierrez, Paolo Fadda, Flavia Pichiorri, Enrico Caserta, Craig C Hofmeister, Marta Chesi, P Leif Bergsagel, Don Morris, Qiao Shi, Matt Coffey, Chandini Thirukkumaran
Acute reoviral infection has been extensively studied given the virus's propensity to target malignant cells and activate caspase-3 mediated apoptosis. Reovirus infection of malignant N1E-115 mouse neuroblastoma cells led to significant increased expression of importin-β and exportin-5 mRNAs (qRTPCR) and proteins (immunohistochemistry) which was partially blocked by small interfering LNA oligomers directed against the reoviral genome. Co-expression analysis showed that the N1E-115 cells that contained reoviral capsid protein had accumulated importin-β and exportin-5, as well as activated caspase 3...
February 2018: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/29389935/novel-pedigree-analysis-implicates-dna-repair-and-chromatin-remodeling-in-multiple-myeloma-risk
#19
Rosalie G Waller, Todd M Darlington, Xiaomu Wei, Michael J Madsen, Alun Thomas, Karen Curtin, Hilary Coon, Venkatesh Rajamanickam, Justin Musinsky, David Jayabalan, Djordje Atanackovic, S Vincent Rajkumar, Shaji Kumar, Susan Slager, Mridu Middha, Perrine Galia, Delphine Demangel, Mohamed Salama, Vijai Joseph, James McKay, Kenneth Offit, Robert J Klein, Steven M Lipkin, Charles Dumontet, Celine M Vachon, Nicola J Camp
The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs...
February 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29389884/long-non-coding-rnas-in-multiple-myeloma
#20
REVIEW
Lucia Nobili, Domenica Ronchetti, Luca Agnelli, Elisa Taiana, Cristina Vinci, Antonino Neri
Multiple myeloma (MM) is an incurable disease caused by the malignant proliferation of bone marrow plasma cells, whose pathogenesis remains largely unknown. Although a large fraction of the genome is actively transcribed, most of the transcripts do not serve as templates for proteins and are referred to as non-coding RNAs (ncRNAs), broadly divided into short and long transcripts on the basis of a 200-nucleotide threshold. Short ncRNAs, especially microRNAs, have crucial roles in virtually all types of cancer, including MM, and have gained importance in cancer diagnosis and prognosis, predicting the response to therapy and, notably, as innovative therapeutic targets...
February 1, 2018: Genes
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