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Myeloma genomics

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https://www.readbyqxmd.com/read/27909306/rpl5-on-1p22-1-is-recurrently-deleted-in-multiple-myeloma-and-its-expression-is-linked-to-bortezomib-response
#1
I J F Hofman, M Van Duin, E De Bruyne, L Fancello, G Mulligan, E Geerdens, E Garelli, C Mancini, H Lemmens, M Delforge, P Vandenberghe, I Wlodarska, A Aspesi, L Michaux, K Vanderkerken, P Sonneveld, K De Keersmaecker
Chromosomal region 1p22 is deleted in ⩾20% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression...
December 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27903915/max-is-an-epigenetic-sensor-of-5-carboxylcytosine-and-is-altered-in-multiple-myeloma
#2
Dongxue Wang, Hideharu Hashimoto, Xing Zhang, Benjamin G Barwick, Sagar Lonial, Lawrence H Boise, Paula M Vertino, Xiaodong Cheng
The oncogenic transcription factor MYC and its binding partner MAX regulate gene expression by binding to DNA at enhancer-box (E-box) elements 5'-CACGTG-3'. In mammalian genomes, the central E-box CpG has the potential to be methylated at the 5-position of cytosine (5mC), or to undergo further oxidation to the 5-hydroxymethyl (5hmC), 5-formyl (5fC), or 5-carboxyl (5caC) forms. We find that MAX exhibits the greatest affinity for a 5caC or unmodified C-containing E-box, and much reduced affinities for the corresponding 5mC, 5hmC or 5fC forms...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27882933/multiple-myeloma-risk-variant-at-7p15-3-creates-an-irf4-binding-site-and-interferes-with-cdca7l-expression
#3
Ni Li, David C Johnson, Niels Weinhold, James B Studd, Giulia Orlando, Fabio Mirabella, Jonathan S Mitchell, Tobias Meissner, Martin Kaiser, Hartmut Goldschmidt, Kari Hemminki, Gareth J Morgan, Richard S Houlston
Genome-wide association studies have identified several risk loci for multiple myeloma (MM); however, the mechanisms by which they influence MM are unknown. Here by using genetic association data and functional characterization, we demonstrate that rs4487645 G>T, the most highly associated variant (P = 5.30 × 10(-25)), resides in an enhancer element 47 kb upstream of the transcription start site of c-Myc-interacting CDCA7L. The G-risk allele, associated with increased CDCA7L expression (P=1.95 × 10(-36)), increases IRF4 binding and the enhancer interacts with the CDCA7L promoter...
November 24, 2016: Nature Communications
https://www.readbyqxmd.com/read/27863261/a-next-generation-sequencing-strategy-for-evaluating-the-most-common-genetic-abnormalities-in-multiple-myeloma
#4
Cristina Jiménez, María Jara-Acevedo, Luis A Corchete, David Castillo, Gonzalo R Ordóñez, M Eugenia Sarasquete, Noemí Puig, Joaquín Martínez-López, M Isabel Prieto-Conde, María García-Álvarez, M Carmen Chillón, Ana Balanzategui, Miguel Alcoceba, Albert Oriol, Laura Rosiñol, Luis Palomera, Ana I Teruel, Juan J Lahuerta, Joan Bladé, María V Mateos, Alberto Orfão, Jesús F San Miguel, Marcos González, Norma C Gutiérrez, Ramón García-Sanz
Identification and characterization of genetic alterations are essential for diagnosis of multiple myeloma and may guide therapeutic decisions. Currently, genomic analysis of myeloma to cover the diverse range of alterations with prognostic impact requires fluorescence in situ hybridization (FISH), single nucleotide polymorphism arrays, and sequencing techniques, which are costly and labor intensive and require large numbers of plasma cells. To overcome these limitations, we designed a targeted-capture next-generation sequencing approach for one-step identification of IGH translocations, V(D)J clonal rearrangements, the IgH isotype, and somatic mutations to rapidly identify risk groups and specific targetable molecular lesions...
November 15, 2016: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/27833099/proteomic-characterization-of-the-world-trade-center-dust-activated-mdig-and-c-myc-signaling-circuit-linked-to-multiple-myeloma
#5
Kai Wu, Lingzhi Li, Chitra Thakur, Yongju Lu, Xiangmin Zhang, Zhengping Yi, Fei Chen
Several epidemiological studies suggested an increased incidence rate of multiple myeloma (MM) among first responders and other individuals who exposed to World Trade Center (WTC) dust. In this report, we provided evidence showing that WTC dust is potent in inducing mdig protein and/or mRNA in bronchial epithelial cells, B cells and MM cell lines. An increased mdig expression in MM bone marrow was observed, which is associated with the disease progression and prognosis of the MM patients. Through integrative genomics and proteomics approaches, we further demonstrated that mdig directly interacts with c-myc and JAK1 in MM cell lines, which contributes to hyperactivation of the IL-6-JAK-STAT3 signaling important for the pathogenesis of MM...
November 11, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27811368/integrative-analysis-of-dna-copy-number-dna-methylation-and-gene-expression-in-multiple-myeloma-reveals-alterations-related-to-relapse
#6
Patryk Krzeminski, Luis A Corchete, Juan L García, Lucía López-Corral, Encarna Fermiñán, Eva M García, Ana A Martín, Jesús M Hernández-Rivas, Ramón García-Sanz, Jesús F San Miguel, Norma C Gutiérrez
Multiple myeloma (MM) remains incurable despite the introduction of novel agents, and a relapsing course is observed in most patients. Although the development of genomic technologies has greatly improved our understanding of MM pathogenesis, the mechanisms underlying relapse have been less thoroughly investigated. In this study, an integrative analysis of DNA copy number, DNA methylation and gene expression was conducted in matched diagnosis and relapse samples from MM patients. Overall, the acquisition of abnormalities at relapse was much more frequent than the loss of lesions present at diagnosis, and DNA losses were significantly more frequent in relapse than in diagnosis samples...
November 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27807282/genetic-interrogation-of-circulating-multiple-myeloma-cells-at-single-cell-resolution
#7
Jens G Lohr, Sora Kim, Joshua Gould, Birgit Knoechel, Yotam Drier, Matthew J Cotton, Daniel Gray, Nicole Birrer, Bang Wong, Gavin Ha, Cheng-Zhong Zhang, Guangwu Guo, Matthew Meyerson, Andrew J Yee, Jesse S Boehm, Noopur Raje, Todd R Golub
Multiple myeloma (MM) remains an incurable disease, with a treatment-refractory state eventually developing in all patients. Constant clonal evolution and genetic heterogeneity of MM are a likely explanation for the emergence of drug-resistant disease. Monitoring of MM genomic evolution on therapy by serial bone marrow biopsy is unfortunately impractical because it involves an invasive and painful procedure. We describe how noninvasive and highly sensitive isolation and characterization of circulating tumor cells (CTCs) from peripheral blood at single-cell resolution recapitulate MM in the bone marrow...
November 2, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27782060/identification%C3%A2-of%C3%A2-long%C3%A2-non-coding%C3%A2-rnas-deregulated%C3%A2-in%C3%A2-multiple%C3%A2-myeloma%C3%A2-cells%C3%A2-resistant%C3%A2-to-proteasome%C3%A2-inhibitors
#8
Ehsan Malek, Byung-Gyu Kim, James J Driscoll
While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance...
October 6, 2016: Genes
https://www.readbyqxmd.com/read/27775669/towards-stratified-medicine-in-plasma-cell-myeloma
#9
REVIEW
Philip Egan, Stephen Drain, Caroline Conway, Anthony J Bjourson, H Denis Alexander
Plasma cell myeloma is a clinically heterogeneous malignancy accounting for approximately one to 2% of newly diagnosed cases of cancer worldwide. Treatment options, in addition to long-established cytotoxic drugs, include autologous stem cell transplant, immune modulators, proteasome inhibitors and monoclonal antibodies, plus further targeted therapies currently in clinical trials. Whilst treatment decisions are mostly based on a patient's age, fitness, including the presence of co-morbidities, and tumour burden, significant scope exists for better risk stratification, sub-classification of disease, and predictors of response to specific therapies...
October 21, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27775078/loss-of-cyld-expression-unleashes-wnt-signaling-in-multiple-myeloma-and-is-associated-with-aggressive-disease
#10
H van Andel, K A Kocemba, A de Haan-Kramer, C H Mellink, M Piwowar, A Broijl, M van Duin, P Sonneveld, M M Maurice, M J Kersten, M Spaargaren, S T Pals
Deletion or mutation of the gene encoding the deubiquitinating enzyme CYLD is a common genomic aberration in multiple myeloma (MM). However, the functional consequence of CYLD loss and the mechanism underlying its putative role as a tumor suppressor gene in the pathogenesis of MM has not been established. Here, we show that CYLD expression is highly variable in myeloma cell lines and primary MMs and that low CYLD expression is associated with disease progression from monoclonal gammopathy of undetermined significance to MM, and with poor overall and progression free-survival of MM patients...
October 24, 2016: Oncogene
https://www.readbyqxmd.com/read/27759436/primary-plasma-cell-leukemia-2-0-advances-in-biology-and-clinical-management
#11
Antonino Neri, Katia Todoerti, Marta Lionetti, Vittorio Simeon, Marzia Barbieri, Filomena Nozza, Gabriella Vona, Alessandra Pompa, Luca Baldini, Pellegrino Musto
Primary plasma cell leukemia (PPCL) is a rare and aggressive variant of multiple myeloma. The introduction of novel agents and modern technologies has recently partially changed the clinical and biological scenario of this malignancy, allowing limited, but not negligible, progresses. Areas covered: We will discuss the complex landscape of genetic alterations in PPCL, derived from conventional and high-throughput technologies; the best available treatments for PPCL; the possible future therapeutic perspectives...
October 19, 2016: Expert Review of Hematology
https://www.readbyqxmd.com/read/27754828/small-interfering-rna-mediated-silencing-of-nicotinamide-phosphoribosyltransferase-nampt-and-lysosomal-trafficking-regulator-lyst-induce-growth-inhibition-and-apoptosis-in-human-multiple-myeloma-cells-a-preliminary-study
#12
Ivyna Pau Ni Bong, Ching Ching Ng, Shaik Kamal Fakiruddin, Moon Nian Lim, Zubaidah Zakaria
Multiple myeloma (MM) is a malignancy of B lymphocytes or plasma cells. Our array-based comparative genomic hybridization findings revealed chromosomal gains at 7q22.3 and 1q42.3, where nicotinamide (NAM) phosphoribosyltransferase (NAMPT) and lysosomal trafficking regulator (LYST) genes are localized, respectively. This led us to further study the functions of these genes in myeloma cells. NAMPT is a key enzyme involved in nicotinamide adenine dinucleotide salvage pathway, and it is frequently overexpressed in human cancers...
November 10, 2016: Bosnian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/27750397/array-cgh-predicts-prognosis-in-plasma-cell-post-transplantation-lymphoproliferative-disorders
#13
Clémentine Sarkozy, Sophie Kaltenbach, Pierre Faurie, Danielle Canioni, Françoise Berger, Alexandra Traverse-Glehen, Hervé Ghesquieres, Gilles Salles, Emmanuel Bachy, Marie-Alexandra Alyanakian, Olivier Hermine, Bénédicte Neven, Elizabeth Macintyre, Serge Romana, Thierry Jo Molina, Felipe Suarez, Vahid Asnafi, Julie Bruneau
Plasma-cell post-transplantation lymphoproliferative disorder (PC-PTLD) is a rare monomorphic PTLD entity divided into plasma cell myeloma (PCM) and plasmacytoma-like lesion (PLL) PTLD. To date, there are no exhaustive published cytogenetic data on PC-PTLD. We report array-based comparative genomic hybridization (aCGH) of 10 cases of PCM and PLL-PTLD. Patients had received kidney (n=6), heart (n=2), lung (n=1) or bone marrow (n=1) transplantation. There were six men and median age at time of PTLD was 56.5 years (3-74)...
October 17, 2016: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/27723723/microenvironment-dependent-growth-of-preneoplastic-and-malignant-plasma-cells-in-humanized-mice
#14
Rituparna Das, Till Strowig, Rakesh Verma, Srinivas Koduru, Anja Hafemann, Stephanie Hopf, Mehmet H Kocoglu, Chiara Borsotti, Lin Zhang, Andrew Branagan, Elizabeth Eynon, Markus G Manz, Richard A Flavell, Madhav V Dhodapkar
Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes...
November 2016: Nature Medicine
https://www.readbyqxmd.com/read/27718532/identification-of-mirsnps-associated-with-the-risk-of-multiple-myeloma
#15
Angelica Macauda, Diego Calvetti, Giuseppe Maccari, Kari Hemminki, Asta Försti, Hartmut Goldschmidt, Niels Weinhold, Richard Houlston, Vibeke Andersen, Ulla Vogel, Gabriele Buda, Judit Varkonyi, Anna Sureda, Joaquin Martinez Lopez, Marzena Watek, Aleksandra Butrym, Maria Eugenia Sarasquete, Marek Dudziński, Artur Jurczyszyn, Agnieszka Druzd-Sitek, Marcin Kruszewski, Edyta Subocz, Mario Petrini, Elzbieta Iskierka-Jażdżewska, Malgorzata Raźny, Gergely Szombath, Herlander Marques, Daria Zawirska, Dominik Chraniuk, Janusz Halka, Svend Erik Hove Jacobsen, Grzegorz Mazur, Ramón García Sanz, Charles Dumontet, Victor Moreno, Anna Stępień, Katia Beider, Matteo Pelosini, Rui Manuel Reis, Malgorzata Krawczyk-Kulis, Marcin Rymko, Hervé Avet-Loiseau, Fabienne Lesueur, Norbert Grząśko, Olga Ostrovsky, Krzysztof Jamroziak, Annette J Vangsted, Andrés Jerez, Waldemar Tomczak, Jan Maciej Zaucha, Katalin Kadar, Juan Sainz, Arnon Nagler, Stefano Landi, Federica Gemignani, Federico Canzian
Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression...
October 8, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27709552/a-new-ten-gene-risk-fraction-model-serving-as-prognostic-indicator-for-clinical-outcome-of-multiple-myeloma
#16
Ai-Xin Hu, Zhi-Yong Huang, Ping Liu, Tian Xiang, Shi Yan, Li Zhang
Multiple myeloma (MM) is a kind of aggressive tumor prevalent with high heterogeneity. Abnormal expression of certain genes may lead to the occurrence and development of MM. Nowadays, it is not commonly seen in clinical research to predict the prognostic circumstances of patients with MM by multiple gene expression profiling method. Identification of potential genes in prognostic process could be beneficial for clinical management of MM. Therefore, we aimed to build a risk fraction model to screen out the prognostic indicator for clinical outcome of MM...
October 5, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27696257/epigenetics-in-multiple-myeloma
#17
Siobhan V Glavey, Salomon Manier, Antonio Sacco, Karma Salem, Yawara Kawano, Juliette Bouyssou, Irene M Ghobrial, Aldo M Roccaro
Multiple myeloma is characterized by clonal proliferation of plasma cells within the bone marrow resulting in anemia, lytic bone lesions, hypercalcemia, and renal impairment. Despite advanced in our understanding of this complex disease in recent years, it is still considered an incurable malignancy. This is, in part, due to the highly heterogenous genomic and phenotypic nature of the disease, which is to date incompletely understood. It is clear that a deeper level of knowledge of the biological events underlying the development of these diseases is needed to identify new targets and generate effective novel therapies...
2016: Cancer Treatment and Research
https://www.readbyqxmd.com/read/27696256/genomic-aberrations-in-multiple-myeloma
#18
Salomon Manier, Karma Salem, Siobhan V Glavey, Aldo M Roccaro, Irene M Ghobrial
Multiple myeloma (MM) is a genetically complex disease. The past few years have seen an evolution in cancer research with the emergence of next-generation sequencing (NGS), enabling high throughput sequencing of tumors-including whole exome, whole genome, RNA, and single-cell sequencing as well as genome-wide association study (GWAS). A few inherited variants have been described, counting for some cases of familial disease. Hierarchically, primary events in MM can be divided into hyperdiploid (HDR) and nonhyperdiploid subtypes...
2016: Cancer Treatment and Research
https://www.readbyqxmd.com/read/27688163/predicting-pd-l1-expression-on-human-cancer-cells-using-next-generation-sequencing-information-in-computational-simulation-models
#19
Emily A Lanzel, M Paula Gomez Hernandez, Amber M Bates, Christopher N Treinen, Emily E Starman, Carol L Fischer, Deepak Parashar, Janet M Guthmiller, Georgia K Johnson, Taher Abbasi, Shireen Vali, Kim A Brogden
PURPOSE: Interaction of the programmed death-1 (PD-1) co-receptor on T cells with the programmed death-ligand 1 (PD-L1) on tumor cells can lead to immunosuppression, a key event in the pathogenesis of many tumors. Thus, determining the amount of PD-L1 in tumors by immunohistochemistry (IHC) is important as both a diagnostic aid and a clinical predictor of immunotherapy treatment success. Because IHC reactivity can vary, we developed computational simulation models to accurately predict PD-L1 expression as a complementary assay to affirm IHC reactivity...
September 29, 2016: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/27634910/recurrent-mutations-of-mapk-pathway-genes-in-multiple-myeloma-but-not-in-amyloid-light-chain-amyloidosis
#20
Seok Jin Kim, Hyun-Tae Shin, Hae-Ock Lee, Nayoung K D Kim, Jae Won Yun, Jee Hyang Hwang, Kihyun Kim, Woong-Yang Park
Clinically applicable platforms revealing actionable genomic alterations may improve the treatment efficacy of myeloma patients. In this pilot study, we used a high depth targeted sequencing panel containing 83 anti-cancer drug target genes to sequence genomic DNAs extracted from bone marrow aspirates of 23 patients with myeloma and 12 patients with amyloid light-chain (AL) amyloidosis. Mutation analysis revealed NRAS as the most commonly mutated gene (30%, 7/23) in myeloma patients followed by KRAS (26%, 6/23) and BRAF (22%, 5/23)...
September 15, 2016: Oncotarget
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