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Myeloma genomics

Vallari Shah, David C Johnson, Amy L Sherborne, Sidra Ellis, Frances M Aldridge, Julie Howard-Reeves, Farzana Begum, Amy Price, Jack Kendall, Laura Chiecchio, Suvi Savola, Matthew W Jenner, Mark T Drayson, Roger G Owen, Walter M Gregory, Gareth J Morgan, Faith E Davies, Richard S Houlston, Gordon Cook, David A Cairns, Graham Jackson, Martin F Kaiser
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 TP53 copy number, we profiled tumours from 1,777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Sub-clonal TP53 deletions were independently associated with shorter overall survival with a hazard ratio of 1.8 (95% CI: 1.2-2.8; P=0.01). Clonal, but not sub-clonal, TP53 deletion were associated with clinical markers of advanced disease, specifically lower platelet counts (P<0...
October 29, 2018: Blood
Tabish Hussain, Bin Liu, Morgan S Shrock, Terence Williams, C Marcelo Aldaz
WWOX is one of the largest human genes spanning over 1.11 Mbp in length at chr16q23.1-q23.2 and containing FRA16D, the second most common chromosomal fragile site (CFS). FRA16D is a hotspot of genomic instability, prone to breakage and for causing germline and somatic copy number variants (CNVs). Consequentially WWOX is frequent target for deletions in cancer. Esophageal, stomach, colon, bladder, ovarian and uterine cancers are those most commonly affected by WWOX deep focal deletions. WWOX deletions significantly correlate with various clinicopathological features in esophageal carcinoma...
October 23, 2018: Genes, Chromosomes & Cancer
Linda B Baughn, Kathryn Pearce, Dirk Larson, Mei-Yin Polley, Eran Elhaik, Michael Baird, Colin Colby, Joanne Benson, Zhuo Li, Yan Asmann, Terry Therneau, James R Cerhan, Celine M Vachon, A Keith Stewart, P Leif Bergsagel, Angela Dispenzieri, Shaji Kumar, S Vincent Rajkumar
Multiple myeloma (MM) is two- to three-fold more common in African Americans (AAs) compared to European Americans (EAs). This striking disparity, one of the highest of any cancer, may be due to underlying genetic predisposition between these groups. There are multiple unique cytogenetic subtypes of MM, and it is likely that the disparity is associated with only certain subtypes. Previous efforts to understand this disparity have relied on self-reported race rather than genetic ancestry, which may result in bias...
October 10, 2018: Blood Cancer Journal
Ken Maes, Bram Boeckx, Philip Vlummens, Kim De Veirman, Eline Menu, Karin Vanderkerken, Diether Lambrechts, Elke De Bruyne
Murine models for multiple myeloma (MM) are often used to investigate pathobiology of multiple myeloma and disease progression. Unlike transgenic mice models, where it is known which oncogene is driving MM disease, the somatic aberrations of spontaneous syngeneic 5T models of MM have not yet been reported. Here, we analyzed the copy-number alterations (CNA) and mutational landscape of 5T2, 5T33vv and 5TGM1 murine MM models using whole-genome and whole-exome sequencing. Forty four percent of the genome of 5T2 cells is affected by CNAs while this was only 11% and 17% for 5T33vv and 5TGM1 cells, respectively...
October 9, 2018: Scientific Reports
Subodh Kumar, Srikanth Talluri, Jagannath Pal, Xiaoli Yuan, Renquan Lu, Puru Nanjappa, Mehmet K Samur, Nikhil C Munshi, Masood A Shammas
We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance. We now demonstrate that base excision repair (BER) associated apurinic/apyrimidinic (AP) nucleases (APEX1 and APEX2) contribute to regulation of HR in MM cells. Transgenic as well as chemical inhibition of APEX1 and/or APEX2 inhibits HR activity in MM cells, whereas the overexpression of either nuclease in normal human cells, increases HR activity...
September 25, 2018: Blood Cancer Journal
Yan-Fang Wang, Hua Wang, Lian-Yong Xi, Zhen-Hao Zhang, Jing Wang, Fei Dong, Xiao-Yan Ke
OBJECTIVE: To detect the molecular cytogenetic abnormalities of multiple myeloma (MM) by using microrray-based comparative genomic hybridization (array-CGH) technology and to investigate its value of application in MM. METHODS: The whole-genoine copy number variants (CNV) of bone marrow samples acquired from 20 cases of newly diagnosed MM patients were detected by genome-wide hybridization and scanning by CytoScan 750K Array (Affymetrix). At the same time, the chromosome abnormalities of bone marrow cells were detected by karyotype analysis and FISH using 9 specific probes: D13S319, RB1, p53, 1q21, IgH, IgH/CCND1, IgH/FGFR3, IgH/MAF, IgH/MAFB...
October 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Zsuzsanna Kovacs, Andras Guttman
Multiple myeloma (MM) is characterized as the clonal proliferation of malignant plasma B-lymphocytes and even as of today, it is an incurable disease. MM accounts for approximately 10% of all hematologic cancers. Its molecular pathogenesis is poorly understood, but the bone marrow microenvironment of tumor cells and genetic factors have apparent roles in the process. Accurate diagnosis is important to properly identify and stratify the disease, however, MM identification steps are time-consuming and expensive...
October 8, 2018: Current Molecular Medicine
Jianxin Yuan, Shuwei Zhang, Yiguo Zhang
Transcription factor Nrf1 acts as a unique vital player in maintaining cellular homeostasis and organ integrity during normal development and growth throughout the life process. Loss-of-function of Nrf1 results in severe oxidative stress, genomic instability, embryonic lethality, developmental disorders, and adult diseases such as non-alcoholic steatohepatitis, hepatocellular carcinoma, diabetes and neurogenerative diseases. Thereby, Nrf1 is critically implicated in a variety of important physio-pathological processes by governing robust target genes in order to reinforce antioxidant, detoxification and cytoprotective responses to cellular stress...
September 26, 2018: Toxicology and Applied Pharmacology
Katia Todoerti, Giovanni Calice, Stefania Trino, Vittorio Simeon, Marta Lionetti, Martina Manzoni, Sonia Fabris, Marzia Barbieri, Alessandra Pompa, Luca Baldini, Valentina Bollati, Pietro Zoppoli, Antonino Neri, Pellegrino Musto
Primary plasma cell leukemia (pPCL) is a rare and very aggressive variant of multiple myeloma (MM). Specific clinical, biological and molecular patterns distinguish pPCL from MM. Here, we performed a genome-wide methylation analysis by high-density array in 14 newly diagnosed pPCL patients along with 60 MMs, and 5 patients affected by monoclonal gammopathy of uncertain significance (MGUS). Our analysis revealed a global hypomethylation profile associated with pPCL. Additionally, differential methylation patterns were found related to distinct chromosomal aberrations and DIS3 mutations, affecting genes with roles in bone metabolism, cell migration, transcription regulation or DNA damage response...
October 2018: Leukemia Research
Aurore Perrot, Jill Corre, Hervé Avet-Loiseau
In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains...
May 23, 2018: American Society of Clinical Oncology Educational Book
Pasquale L Fedele, Simon N Willis, Yang Liao, Michael S Low, Jai Rautela, David H Segal, Jia-Nan Gong, Nicholas D Huntington, Wei Shi, David C S Huang, George Grigoriadis, Julie Tellier, Stephen L Nutt
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis...
September 18, 2018: Blood
Molly Went, Amit Sud, Asta Försti, Britt-Marie Halvarsson, Niels Weinhold, Scott Kimber, Mark van Duin, Gudmar Thorleifsson, Amy Holroyd, David C Johnson, Ni Li, Giulia Orlando, Philip J Law, Mina Ali, Bowang Chen, Jonathan S Mitchell, Daniel F Gudbjartsson, Rowan Kuiper, Owen W Stephens, Uta Bertsch, Peter Broderick, Chiara Campo, Obul R Bandapalli, Hermann Einsele, Walter A Gregory, Urban Gullberg, Jens Hillengass, Per Hoffmann, Graham H Jackson, Karl-Heinz Jöckel, Ellinor Johnsson, Sigurður Y Kristinsson, Ulf-Henrik Mellqvist, Hareth Nahi, Douglas Easton, Paul Pharoah, Alison Dunning, Julian Peto, Federico Canzian, Anthony Swerdlow, Rosalind A Eeles, ZSofia Kote-Jarai, Kenneth Muir, Nora Pashayan, Jolanta Nickel, Markus M Nöthen, Thorunn Rafnar, Fiona M Ross, Miguel Inacio da Silva Filho, Hauke Thomsen, Ingemar Turesson, Annette Vangsted, Niels Frost Andersen, Anders Waage, Brian A Walker, Anna-Karin Wihlborg, Annemiek Broyl, Faith E Davies, Unnur Thorsteinsdottir, Christian Langer, Markus Hansson, Hartmut Goldschmidt, Martin Kaiser, Pieter Sonneveld, Kari Stefansson, Gareth J Morgan, Kari Hemminki, Björn Nilsson, Richard S Houlston
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism...
September 13, 2018: Nature Communications
Giulia Biancon, Silvia Gimondi, Antonio Vendramin, Cristiana Carniti, Paolo Corradini
Novel treatments for multiple myeloma (MM) have increased rates of complete response, raising interest in more accurate methods to evaluate residual disease. Cell-free tumor DNA (cfDNA) analysis may represent a minimally invasive approach complementary to multiparameter flow cytometry (MFC) and molecular methods on bone marrow aspirates. A sequencing approach using the Ion Torrent Personal Genome Machine was applied to identify clonal IGH gene rearrangements in tumor plasma cells (PCs) and in serial plasma samples of 25 patients with MM receiving second-line therapy...
November 2018: Journal of Molecular Diagnostics: JMD
Niccolò Bolli, Francesco Maura, Stephane Minvielle, Dominik Gloznik, Raphael Szalat, Anthony Fullam, Inigo Martincorena, Kevin J Dawson, Mehmet Kemal Samur, Jorge Zamora, Patrick Tarpey, Helen Davies, Mariateresa Fulciniti, Masood A Shammas, Yu Tzu Tai, Florence Magrangeas, Philippe Moreau, Paolo Corradini, Kenneth Anderson, Ludmil Alexandrov, David C Wedge, Herve Avet-Loiseau, Peter Campbell, Nikhil Munshi
We analyzed whole genomes of unique paired samples from smoldering multiple myeloma (SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a "static progression model", where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects the time needed to accumulate a sufficient disease burden; and a "spontaneous evolution model", where a change in the subclonal composition is observed...
August 22, 2018: Nature Communications
Subhayan Chattopadhyay, Hauke Thomsen, Miguel Inacio da Silva Filho, Niels Weinhold, Per Hoffmann, Markus M Nöthen, Arendt Marina, Karl-Heinz Jöckel, Börge Schmidt, Sonali Pechlivanis, Christian Langer, Hartmut Goldschmidt, Kari Hemminki, Asta Försti
BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways. METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls)...
June 11, 2018: Molecular Medicine
Mette Dahl, Lasse Sommer Kristensen, Kirsten Grønbæk
With the introduction of next generation sequencing methods, such as RNA sequencing, it has become apparent that alterations in the non-coding regions of our genome are important in the development of cancer. Particularly interesting is the class of long non-coding RNAs (lncRNAs), including the recently described subclass of circular RNAs (circRNAs), which display tissue- and cell-type specific expression patterns and exert diverse regulatory functions in the cells. B-cells undergo complex and tightly regulated processes in order to develop from antigen naïve cells residing in the bone marrow to the highly diverse and competent effector cells circulating in peripheral blood...
August 21, 2018: International Journal of Molecular Sciences
Ziyan Wang, Yuqing Yuan, Liying Zhang, Zhou Min, Dongming Zhou, Sun Yu, Panjun Wang, Songguang Ju, Li Jun, Jinxiang Fu
Background: Mesenchymal stem cells (MSCs) represent a subset of non-hematopoietic adult stem cells, which can also fuse with other cells spontaneously in bone marrow and capable of adopting the phenotype of other cells. The fusion of somatic cells with stem cells can reprogram somatic cells to a pluripotent state. Our research on the fusion of bone marrow mesenchymal stem cells(BM-MSCs) and MM cells demonstrate that the fused cells can exhibit stemness and cancer cell-like characteristics...
July 24, 2018: Oncotarget
Daniele Caracciolo, Maria Teresa Di Martino, Nicola Amodio, Eugenio Morelli, Martina Montesano, Cirino Botta, Francesca Scionti, Daniela Talarico, Emanuela Altomare, Maria Eugenia Gallo Cantafio, Valeria Zuccalà, Lorenza Maltese, Katia Todoerti, Marco Rossi, Mariamena Arbitrio, Antonino Neri, Pierosandro Tagliaferri, Pierfrancesco Tassone
Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation...
August 17, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Seyed Hamidreza Mahmoudpour, Obul Reddy Bandapalli, Miguel Inácio da Silva Filho, Chiara Campo, Kari Hemminki, Hartmut Goldschmidt, Maximilian Merz, Asta Försti
BACKGROUND: Based on the possible shared mechanisms of chemotherapy-induced peripheral neuropathy (CIPN) for different drugs, we aimed to aggregate results of all previously published genome-wide association studies (GWAS) on CIPN, and to replicate them within a cohort of multiple myeloma (MM) patients. METHODS: Following a systematic literature search, data for CIPN associated single nucleotide polymorphisms (SNPs) with P-values< 10- 5 were extracted; these associations were investigated within a cohort of 983 German MM patients treated with bortezomib, thalidomide or vincristine...
August 15, 2018: BMC Cancer
Szabolcs Kosztolanyi, Richard Kiss, Lilit Atanesyan, Ambrus Gango, Karel de Groot, Maryvonne Steenkamer, Pal Jakso, Andras Matolcsy, Bela Kajtar, Laszlo Pajor, Karoly Szuhai, Suvi Savola, Csaba Bodor, Donat Alpar
Multiple myeloma (MM) is a genetically heterogeneous disease with a diverse clinical outcome. Copy number alterations (CNAs), including whole chromosome and subchromosomal gains and losses, are common contributors of the pathogenesis and have demonstrated prognostic impact in MM. We tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA), a novel technique combining MLPA and next-generation sequencing, to detect disease-related CNAs. Copy number status at 371 genomic loci was simultaneously analyzed in 56 diagnostic bone marrow samples, which were also examined by conventional MLPA and interphase fluorescence in situ hybridization (iFISH)...
August 8, 2018: Journal of Molecular Diagnostics: JMD
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