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Myeloma genomics

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https://www.readbyqxmd.com/read/28642592/integrative-network-analysis-identifies-novel-drivers-of-pathogenesis-and-progression-in-newly-diagnosed-multiple-myeloma
#1
A Laganà, D Perumal, D Melnekoff, B Readhead, B A Kidd, V Leshchenko, P-Y Kuo, J Keats, M DeRome, J Yesil, D Auclair, S Lonial, A Chari, H J Cho, B Barlogie, S Jagannath, J T Dudley, S Parekh
Multiple Myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide clinical and molecular heterogeneity. In this study we applied an integrative network biology approach to molecular and clinical data measured from 450 patients with newly diagnosed MM from the MMRF CoMMpass study. A novel network model of myeloma (MMNet) was constructed, revealing complex molecular disease patterns and novel associations between clinical traits and genomic markers. Genomic alterations and groups of co-expressed genes correlate with disease stage, tumor clonality, and early progression...
June 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28633670/preclinical-anti-myeloma-activity-of-edo-s101-a-new-bendamustine-derived-molecule-with-added-hdaci-activity-through-potent-dna-damage-induction-and-impairment-of-dna-repair
#2
Ana-Alicia López-Iglesias, Ana B Herrero, Marta Chesi, Laura San-Segundo, Lorena González-Méndez, Susana Hernández-García, Irena Misiewicz-Krzeminska, Dalia Quwaider, Montserrat Martín-Sánchez, Daniel Primo, Teresa Paíno, P Leif Bergsagel, Thomas Mehrling, Marcos González-Díaz, Jesús F San-Miguel, María-Victoria Mateos, Norma C Gutiérrez, Mercedes Garayoa, Enrique M Ocio
BACKGROUND: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. METHODS: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents...
June 20, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28610537/overcoming-multiple-myeloma-drug-resistance-in-the-era-of-cancer-omics
#3
Matthew Ho Zhi Guang, Amanda McCann, Giada Bianchi, Li Zhang, Paul Dowling, Despina Bazou, Peter O'Gorman, Kenneth C Anderson
Multiple myeloma (MM) is among the most compelling examples of cancer in which research has markedly improved the length and quality of lives of those afflicted. Research efforts have led to 18 newly approved treatments over the last 12 years, including seven in 2015. However, despite significant improvement in overall survival, MM remains incurable as most patients inevitably, yet unpredictably, develop refractory disease. Recent advances in high-throughput 'omics' techniques afford us an unprecedented opportunity to (1) understand drug resistance at the genomic, transcriptomic, and proteomic level; (2) discover novel diagnostic, prognostic, and therapeutic biomarkers; (3) develop novel therapeutic targets and rational drug combinations; and (4) optimize risk-adapted strategies to circumvent drug resistance, thus bringing us closer to a cure for MM...
June 13, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28580307/liquid-chromatography-mass-spectrometry-based-metabolite-pathway-analyses-of-myeloma-and-non-hodgkin-s-lymphoma-patients
#4
Carl Angelo D Medriano, Jinhyuk Na, Kyung-Min Lim, Jin-Ho Chung, Youngja H Park
OBJECTIVE: This study attempted to identify altered metabolism and pathways related to non-Hodgkin's lymphoma (NHL) and myeloma patients. MATERIALS AND METHODS: In this retrospective study, we collected plasma samples from 11 patients-6 healthy controls with no evidence of any blood cancers and 5 patients with either multiple myeloma (n=3) or NHL (n=2) during the preliminary study period. Samples were analyzed using quadrupole time-of-flight liquid chromatography mass spectrometry (LC-MS)...
2017: Cell Journal
https://www.readbyqxmd.com/read/28565861/global-methylation-and-promoter-specific-methylation-of-the-p16-socs-1-e-cadherin-p73-and-shp-1-genes-and-their-expression-in-patients-with-multiple-myeloma-during-active-disease-and-remission
#5
Déborah Martínez-Baños, Beatríz Sánchez-Hernández, Guadalupe Jiménez, Georgina Barrera-Lumbreras, Olga Barrales-Benítez
Tumor suppressor gene promoter CpG island methylation is a well-recognized mechanism in cancer pathogenesis, but its role in multiple myeloma (MM) is controversial. The present study investigated the methylation status and expression of P16, suppressor of cytokine signaling 1 (SOCS-1), P73, E-cadherin and Src homology region 2 domain-containing phosphatase 1 (SHP-1), as well as global methylation in patients with MM during active disease and remission. Bone marrow samples were obtained from 43 patients at the Multiple Myeloma Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (Mexico City, Mexico) during active disease and remission...
May 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28561666/integration-of-genomics-into-treatment-are-we-there-yet
#6
Gareth J Morgan, John R Jones
Using advances in genetic analysis to segment and direct treatment of multiple myeloma (MM) represents a way of maintaining therapeutic progress. Recent genetic analyses have opened the possibility of enhancing risk stratification approaches and of using different risk and biologic strata as part of clinical trials. The Myeloma Genome Project is a collaborative project that has compiled the largest set of cases with sequencing and have outcome data that are available for stratification purposes. Mutation-targeted treatment of the Ras pathway has been shown to be active in MM, but is compromised by the presence of the subclonal genetic variation typical of myeloma...
2017: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/28550183/somatic-mutation-spectrum-in-monoclonal-gammopathy-of-undetermined-significance-indicates-a-less-complex-genomic-landscape-compared-to-multiple-myeloma
#7
Aneta Mikulasova, Christopher P Wardell, Alexander Murison, Eileen M Boyle, Graham H Jackson, Jan Smetana, Zuzana Kufova, Ludek Pour, Viera Sandecka, Martina Almasi, Pavla Vsianska, Evzen Gregora, Petr Kuglik, Roman Hajek, Faith E Davies, Gareth J Morgan, Brian A Walker
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about the molecular mechanism of malignant transformation. We have performed whole exome sequencing together with CGH+SNP array analysis in 33 flow-cytometry separated abnormal plasma cell samples from MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level...
May 26, 2017: Haematologica
https://www.readbyqxmd.com/read/28544233/bcl6-overexpression-alters-gene-expression-profile-in-a-myeloma-cell-line-and-is-associated-with-decreased-dna-damage-response
#8
Kenichi Tahara, Makiko Takizawa, Arito Yamane, Yohei Osaki, Takuma Ishizaki, Takeki Mitsui, Akihiko Yokohama, Takayuki Saitoh, Norifumi Tsukamoto, Morio Matsumoto, Hirokazu Murakami, Yoshihisa Nojima, Hiroshi Handa
BCL6 attenuates DNA damage response (DDR) through gene repression and facilitates tolerance to genomic instability during immunoglobulin affinity maturation in germinal center (GC) B cells. Although BCL6 expression is repressed through normal differentiation of GC B cells into plasma cells, a recent study showed the ectopic expression of BCL6 in primary multiple myeloma (MM) cells. However, the functional roles of BCL6 in MM cells are largely unknown. Here, we report that overexpression of BCL6 in a MM cell line, KMS12PE, induced transcriptional repression of ataxia telangiectasia mutated (ATM), a DDR signaling kinase, which was associated with a reduction in γH2AX formation after DNA damage...
May 23, 2017: Cancer Science
https://www.readbyqxmd.com/read/28531552/the-role-of-next-generation-sequencing-in-infection-prevention-in-human-parainfluenza-virus-3-infections-in-immunocompromised-patients
#9
Atul Kothari, Mary J Burgess, Juan Carlos Rico Crescencio, Joshua L Kennedy, Jesse L Denson, Kurt C Schwalm, Ashley N Stoner, John C Kincaid, Faith E Davies, Darrell L Dinwiddie
BACKGROUND: Respiratory viral infections are a significant problem in patients with hematologic malignancies. We report a cluster of HPIV 3 infections in our myeloma patients, and describe the utility of next generation sequencing (NGS) to identify transmission linkages which can assist in infection prevention. OBJECTIVES: To evaluate the utility of NGS to track respiratory viral infection outbreaks and delineate between community acquired and nosocomial infections in our cancer units...
May 12, 2017: Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology
https://www.readbyqxmd.com/read/28498490/multi-subgroup-gene-screening-using-semi-parametric-hierarchical-mixture-models-and-the-optimal-discovery-procedure-application-to-a-randomized-clinical-trial-in-multiple-myeloma
#10
Shigeyuki Matsui, Hisashi Noma, Pingping Qu, Yoshio Sakai, Kota Matsui, Christoph Heuck, John Crowley
This article proposes an efficient approach to screening genes associated with a phenotypic variable of interest in genomic studies with subgroups. In order to capture and detect various association profiles across subgroups, we flexibly estimate the underlying effect size distribution across subgroups using a semi-parametric hierarchical mixture model for subgroup-specific summary statistics from independent subgroups. We then perform gene ranking and selection using an optimal discovery procedure based on the fitted model with control of false discovery rate...
May 12, 2017: Biometrics
https://www.readbyqxmd.com/read/28495797/ixazomib-enhances-parathyroid-hormone-pth-induced-%C3%AE-catenin-t-cell-factor-tcf-signaling-by-dissociating-%C3%AE-catenin-from-the-pth-receptor
#11
Yanmei Yang, Hong Lei, Ya-Wei Qiang, Bin Wang
The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) is the first orally administered proteasome inhibitor that was approved recently for the treatment of multiple myeloma in part through inhibition of pathologic bone destruction. Proteasome inhibitors were reported to stabilize β-catenin by ubiquitin-proteasome pathway...
May 11, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28492226/circulating-tumour-dna-sequence-analysis-as-an-alternative-to-multiple-myeloma-bone-marrow-aspirates
#12
Olena Kis, Rayan Kaedbey, Signy Chow, Arnavaz Danesh, Mark Dowar, Tiantian Li, Zhihua Li, Jessica Liu, Mark Mansour, Esther Masih-Khan, Tong Zhang, Scott V Bratman, Amit M Oza, Suzanne Kamel-Reid, Suzanne Trudel, Trevor J Pugh
The requirement for bone-marrow aspirates for genomic profiling of multiple myeloma poses an obstacle to enrolment and retention of patients in clinical trials. We evaluated whether circulating cell-free DNA (cfDNA) analysis is comparable to molecular profiling of myeloma using bone-marrow tumour cells. We report here a hybrid-capture-based Liquid Biopsy Sequencing (LB-Seq) method used to sequence all protein-coding exons of KRAS, NRAS, BRAF, EGFR and PIK3CA in 64 cfDNA specimens from 53 myeloma patients to >20,000 × median coverage...
May 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28466550/cutting-edge-genomics-reveal-new-insights-into-tumour-development-disease-progression-and-therapeutic-impacts-in-multiple-myeloma
#13
REVIEW
Ankit K Dutta, Duncan R Hewett, J Lynn Fink, John P Grady, Andrew C W Zannettino
Multiple Myeloma (MM) is a haematological malignancy characterised by the clonal expansion of plasma cells (PCs) within the bone marrow. Despite advances in therapy, MM remains a largely incurable disease with a median survival of 6 years. In almost all cases, the development of MM is preceded by the benign PC condition Monoclonal Gammopathy of Undetermined Significance (MGUS). Recent studies show that the transformation of MGUS to MM is associated with complex genetic changes. Understanding how these changes contribute to evolution will present targets for clinical intervention...
May 3, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28426555/creating-artificial-lymphoid-tissues-to-study-immunity-and-hematological-malignancies
#14
Shivem B Shah, Ankur Singh
PURPOSE OF REVIEW: The specialized microenvironments of lymphoid tissue affect immune cell function and progression of disease. However, current animal models are low throughput and a large number of human diseases are difficult to model in animals. Animal models are less amenable to manipulation of tissue niche components, signalling pathways, epigenetics, and genome editing than ex vivo models. On the other hand, conventional 2D cultures lack the physiological relevance to study precise microenvironmental interactions...
July 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28385781/monitoring-of-multiple-myeloma-by-quantification-of-recurrent-mutations-in-serum
#15
Even Holth Rustad, Eivind Coward, Emilie R Skytøen, Kristine Misund, Toril Holien, Therese Standal, Magne Børset, Vidar Beisvag, Ola Myklebost, Leonardo A Meza-Zepeda, Hong Yan Dai, Anders Sundan, Anders Waage
Circulating tumor DNA (ctDNA) is a promising biomarker to monitor tumor load and genome alterations. We have explored the presence of ctDNA in multiple myeloma patients and its relation to disease activity during long-term follow-up. We used digital droplet PCR to monitor recurrent mutations, mainly in mitogen activated protein kinase pathway genes NRAS, KRAS and BRAF. Mutations were identified by next generation sequencing or PCR of bone marrow plasma cells, and their presence analyzed in 251 archived serum samples obtained from 20 patients during up to 7 years...
April 6, 2017: Haematologica
https://www.readbyqxmd.com/read/28380360/the-mutational-landscape-of-circulating-tumor-cells-in-multiple-myeloma
#16
Yuji Mishima, Bruno Paiva, Jiantao Shi, Jihye Park, Salomon Manier, Satoshi Takagi, Mira Massoud, Adriana Perilla-Glen, Yosra Aljawai, Daisy Huynh, Aldo M Roccaro, Antonio Sacco, Marzia Capelletti, Alexandre Detappe, Diego Alignani, Kenneth C Anderson, Nikhil C Munshi, Felipe Prosper, Jens G Lohr, Gavin Ha, Samuel S Freeman, Eliezer M Van Allen, Viktor A Adalsteinsson, Franziska Michor, Jesus F San Miguel, Irene M Ghobrial
The development of sensitive and non-invasive "liquid biopsies" presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs) is prognostic in multiple myeloma (MM), but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM) tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM...
April 4, 2017: Cell Reports
https://www.readbyqxmd.com/read/28375557/genomewide-association-study-on-monoclonal-gammopathy-of-unknown-significance-mgus
#17
Hauke Thomsen, Chiara Campo, Niels Weinhold, Miguel Inacio da Silva Filho, Luděk Pour, Evžen Gregora, Pavel Vodicka, Ludmila Vodickova, Per Hoffmann, Markus M Nöthen, Karl-Heinz Jöckel, Christian Langer, Roman Hajek, Hartmut Goldschmidt, Kari Hemminki, Asta Försti
OBJECTIVES: To identify germ line variants contributing to the development of monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant precursor for multiple myeloma (MM). METHODS: We conducted the first genomewide association study (GWAS) on MGUS on 243 German cases with a replication on 294 Czech cases. Identified loci were further analyzed in 1508 German MM patients. New MM loci recently reported in a meta-analysis were also tested in the MGUS GWAS...
April 4, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28360189/biobanking-strategy-and-sample-preprocessing-for-integrative-research-in-monoclonal-gammopathies
#18
T Ševčíková, K Growková, Z Kufová, J Filipová, P Vrublová, T Jelínek, Z Kořístek, F Kryukov, E Kryukova, R Hájek
AIMS: Some types of monoclonal gammopathies are typified by a very limited availability of aberrant cells. Modern research use high throughput technologies and an integrated approach for detailed characterisation of abnormal cells. This strategy requires relatively high amounts of starting material which cannot be obtained from every diagnosis without causing inconvenience to the patient. The aim of this methodological paper is to reflect our long experience with laboratory work and describe the best protocols for sample collection, sorting and further preprocessing in terms of the available number of cells and intended downstream application in monoclonal gammopathies research...
March 30, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28341836/fam46c-is-critical-for-the-anti-proliferation-and-pro-apoptotic-effects-of-norcantharidin-in-hepatocellular-carcinoma-cells
#19
Qiao-Yan Zhang, Xiao-Qiang Yue, Yi-Ping Jiang, Ting Han, Hai-Liang Xin
Norcantharidin (NCTD), a demethylated analog of cantharidin derived from Chinese traditional medicine blister beetle, has been currently used as an anticancer drug for various cancers including hepatocellular carcinoma (HCC). In this study, for a more comprehensive understanding of the targets of NCTD in HCC, next-generation RNA-Seq was utilized. We revealed that the expression of FAM46C, which has been reported as a tumor suppressor for multiple myeloma, was enhanced after NCTD treatment. Re-analysis of TCGA (The Cancer Genome Atlas) LIHC (liver hepatocellular carcinoma) dataset demonstrated that FAM46C expression was significantly lower in HCC tissues than in normal liver tissues...
March 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28317148/bortezomib-induced-peripheral-neuropathy-a-genome-wide-association-study-on-multiple-myeloma-patients
#20
Chiara Campo, Miguel Inacio da Silva Filho, Niels Weinhold, Seyed Hamidreza Mahmoudpour, Hartmut Goldschmidt, Kari Hemminki, Maximilian Merz, Asta Försti
The proteasome-inhibitor bortezomib was introduced into the treatment of multiple myeloma more than a decade ago. It is clinically beneficial, but peripheral neuropathy (PNP) is a side effect that may limit its use in some patients. To examine the possible genetic predisposing factors to PNP, we performed a genome-wide association study on 646 bortezomib-treated German multiple myeloma patients. Our aim was to identify genetic risk variants associated with the development of PNP as a serious side effect of the treatment...
March 20, 2017: Hematological Oncology
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