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Myeloma genomics

Luca Agnelli, Andrea Bisognin, Katia Todoerti, Martina Manzoni, Elisa Taiana, Serena Galletti, Giovanna Cutrona, Enrico Gaffo, Stefania Bortoluzzi, Antonino Neri
Microarray analysis of the multiple myeloma (MM) miRNome has unraveled the differential expression of miRNAs in cytogenetic subgroups, their involvement in the tumor biology and their effectiveness in prognostic models. Herein, the small RNA transcriptional landscape in MM has been investigated exploiting the possibilities offered by small RNA-seq, including accurate quantification of known mature species, discovery and characterization of isomiRs, and miRNA-offset RNAs (moRNAs). Matched small RNA-seq and miRNA GeneChip® microarray expression profiles were obtained in a representative panel of 30 primary MM tumors, fully characterized for genomic aberrations and mutations...
February 19, 2019: Blood Cancer Journal
Molly Went, Amit Sud, Ni Li, David C Johnson, Jonathan S Mitchell, Martin Kaiser, Richard S Houlston
Genomic regions of homozygosity (ROH), detectable in outbred populations, have been implicated as determinants of inherited risk. To examine whether ROH is associated with risk of multiple myeloma (MM), we performed whole-genome homozygosity analysis using single-nucleotide polymorphism genotype data from 2,282 MM cases and 5,197 controls, with replication in an additional 878 MM cases and 7,083 controls. Globally, the distribution of ROH between cases and controls was not significantly different. However, one ROH at chromosome 9q21, harboring the B-cell transcription factor gene KLF9, showed evidence of a consistent association and may therefore warrant further investigation as a candidate risk factor for MM...
February 15, 2019: Annals of Human Genetics
Karissa L Milbury, Biplab Paul, Azra Lari, Claire Fowler, Ben Montpetit, Peter C Stirling
The exosome functions to regulate the cellular transcriptome through RNA biogenesis, surveillance, and decay. Through these activities the exosome contributes to many cellular processes, including ribosome biogenesis, mitosis, transcription, and gene silencing. Mutations in Dis3, a catalytic subunit of the RNA exosome with separable endonuclease and exonuclease activities, have recently been linked to the blood cancer multiple myeloma. Here we report that high-throughput genetic interaction screening of a cancer-associated DIS3 allele, dis3E729K , provides evidence for DIS3 functioning to support mitotic fidelity in yeast...
February 6, 2019: Nucleus
Bingjie Li, Chenxi Liu, Guixue Cheng, Mengle Peng, Xiaosong Qin, Yong Liu, Yongzhe Li, Dongchun Qin
Multiple myeloma (MM) is an extremely complex plasma cell malignancy that is genetically heterogeneous. A recent Genome-wide association study (GWAS) indicated that variation at 2q22 (rs61070260) influences MM risk. This association has not been validated to date in a Chinese Han population. In this study, we evaluated the association between rs61070260 in LRP1B and MM risk in a Chinese Han population involving 739 MM patients and 592 healthy controls. Our results indicated that rs61070260 in LRP1B was significantly associated with MM susceptibility (P=3...
2019: Journal of Cancer
Dickran Kazandjian, Elizabeth Hill, Malin Hultcrantz, Evan H Rustad, Venkata Yellapantula, Theresia Akhlaghi, Neha Korde, Sham Mailankody, Alex Dew, Elli Papaemmanuil, Irina Maric, Mary Kwok, Ola Landgren
Caucasian Americans (CA) compared with African Americans (AA) have a twofold increased incidence of multiple myeloma (MM) and have an earlier age of diagnosis. However, there is sparse information regarding underlying biological differences across racial/ethnic groups. We characterized genetic alterations using a targeted next-generation sequencing assay called myTYPE, developed at MSKCC, allowing capture of somatic mutations, IgH translocations, gains/losses, and hyperdiploidy. Samples were obtained from the NIH Plasma Cell Dyscrasia Racial Disparity Cohort...
February 4, 2019: Blood Cancer Journal
Shaji K Kumar
There has been a paradigm shift in the treatment of myeloma triggered by intense exploration of the disease biology to understand the basis of disease development and progression and the evolution of newly diagnosed myeloma to a multidrug refractory state that is associated with poor survival. These studies have in turn informed us of potential therapeutic strategies in our ongoing effort to cure this disease, or at a minimum convert it into a chronic disease. Given the clonal evolution that leads to development of drug resistance and treatment failure, identification of specific genetic abnormalities and approaches to target these abnormalities have been on the top of the list for some time...
January 2019: Cancer Journal
Jill Corre, Hervé Avet-Loiseau
Although therapeutic strategies have been adapted to age and comorbidities of myeloma patients for a long time, all patients currently experiment the same treatment whatever their genomic risk. However, high-risk patients should benefit right now from the most efficient drugs combinations. Herein, we review and discuss how to optimally define risk to adapt treatment and why a modern multiparametric definition of genomic risk is urgently needed. Minimal residual disease status will probably also take a growing place in patient's management, including in treatment adaptation...
January 2019: Cancer Journal
Taylor Harding, Linda Baughn, Shaji Kumar, Brian Van Ness
Multiple myeloma (MM) is a hematologic malignancy that is considered mostly incurable in large part due to the inability of standard of care therapies to overcome refractory disease and inevitable drug-resistant relapse. The post-genomic era has been a productive period of discovery where modern sequencing methods have been applied to large MM patient cohorts to modernize our current perception of myeloma pathobiology and establish an appreciation for the vast heterogeneity that exists between and within MM patients...
January 25, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Romana Butova, Petra Vychytilova-Faltejskova, Adela Souckova, Sabina Sevcikova, Roman Hajek
Multiple myeloma (MM) is the second most common hematooncological disease of malignant plasma cells in the bone marrow. While new treatment brought unprecedented increase of survival of patients, MM pathogenesis is yet to be clarified. Increasing evidence of expression of long non-coding RNA molecules (lncRNA) linked to development and progression of many tumors suggested their important role in tumorigenesis. To date, over 15,000 lncRNA molecules characterized by diversity of function and specificity of cell distribution were identified in the human genome...
January 24, 2019: Non-Coding RNA
Giao N Lê, Jonathan Bones, Mark Coyne, Despina Bazou, Paul Dowling, Peter O'Gorman, Anne-Marie Larkin
Multiple myeloma, an incurable malignancy of the plasma cells in the bone marrow, has a complex pathogenesis due to clonal heterogeneity. Over the years, many clinical trials and researches have led to the development of effective myeloma treatments, resulting in survival prolongation. Molecular prognostic markers for risk-stratification to predict survival, and predictive markers for treatment response are being extensively explored. This review discusses the current risk-adaptive strategies based on genetic and molecular risk signatures that are in practice to predict survival and describes the future prognostic and predictive biomarkers across the fields of genomics, proteomics, and glycomics in myeloma...
January 17, 2019: Molecular omics
Matthew Ho Zhi Guang, Emma L Kavanagh, Luke Paul Dunne, Paul Dowling, Li Zhang, Sinéad Lindsay, Despina Bazou, Chia Yin Goh, Cathal Hanley, Giada Bianchi, Kenneth C Anderson, Peter O'Gorman, Amanda McCann
Despite significant advances in cancer diagnostics and therapeutics the majority of cancer unfortunately remains incurable, which has led to continued research to better understand its exceptionally diverse biology. As a result of genomic instability, cancer cells typically have elevated proteotoxic stress. Recent appreciation of this functional link between the two secondary hallmarks of cancer: aneuploidy (oxidative stress) and proteotoxic stress, has therefore led to the development of new anticancer therapies targeting this emerging "Achilles heel" of malignancy...
January 9, 2019: Cancers
Molly Went, Amit Sud, Helen Speedy, Nicola J Sunter, Asta Försti, Philip J Law, David C Johnson, Fabio Mirabella, Amy Holroyd, Ni Li, Giulia Orlando, Niels Weinhold, Mark van Duin, Bowang Chen, Jonathan S Mitchell, Larry Mansouri, Gunnar Juliusson, Karin E Smedby, Sandrine Jayne, Aneela Majid, Claire Dearden, David J Allsup, James R Bailey, Guy Pratt, Chris Pepper, Chris Fegan, Richard Rosenquist, Rowan Kuiper, Owen W Stephens, Uta Bertsch, Peter Broderick, Hermann Einsele, Walter M Gregory, Jens Hillengass, Per Hoffmann, Graham H Jackson, Karl-Heinz Jöckel, Jolanta Nickel, Markus M Nöthen, Miguel Inacio da Silva Filho, Hauke Thomsen, Brian A Walker, Annemiek Broyl, Faith E Davies, Markus Hansson, Hartmut Goldschmidt, Martin J S Dyer, Martin Kaiser, Pieter Sonneveld, Gareth J Morgan, Kari Hemminki, Björn Nilsson, Daniel Catovsky, James M Allan, Richard S Houlston
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg  = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk...
December 21, 2018: Blood Cancer Journal
Juraj Adamik, Deborah L Galson, G David Roodman
Multiple myeloma (MM) is the most frequent cancer to involve the skeleton with patients developing osteolytic bone lesions due to hyperactivation of osteoclasts and suppression of BMSCs differentiation into functional osteoblasts. Although new therapies for MM have greatly improved survival, MM remains incurable for most patients. Despite the major advances in current anti-MM and anti-resorptive treatments that can significantly improve osteolytic bone lysis, many bone lesions can persist even after therapeutic remission of active disease...
November 2018: Journal of Bone Oncology
Mariateresa Fulciniti, Charles Y Lin, Mehmet K Samur, Michael A Lopez, Irtisha Singh, Matthew A Lawlor, Raphael E Szalat, Christopher J Ott, Herve' Avet-Loiseau, Kenneth C Anderson, Richard A Young, James E Bradner, Nikhil C Munshi
The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells...
December 26, 2018: Cell Reports
Natalie Galanina, Rafael Bejar, Michael Choi, Aaron Goodman, Matthew Wieduwilt, Carolyn Mulroney, Lisa Kim, Huwate Yeerna, Pablo Tamayo, Jo-Anne Vergilio, Tariq I Mughal, Vincent Miller, Catriona Jamieson, Razelle Kurzrock
Background : The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. Methods : We describe 235 patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and their potential actionability. Results : Overall, 227 patients (96.5%) had adequate tissue. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17...
December 21, 2018: Cancers
Gurvinder Kaur, Ritu Gupta, Nitin Mathur, Lata Rani, Lalit Kumar, Atul Sharma, Vishwajeet Singh, Anubha Gupta, Om Dutt Sharma
Complex Chromosomal Rearrangements (CCRs) are increasingly being reported as genetic risk factors of clinical significance in cancer owing to their identification using high resolution whole genome profiling technologies. This study employed high resolution CGH + SNP microarrays for whole genome copy number variations (CNV) profiling and identified CCRs in 11/107(10%) newly diagnosed Multiple Myeloma (MM) patients. Six patients exhibited Chromothripsis (CTH) among seven chromosomes that were confirmed with automated CTLPscanner web tool and; five cases displayed chromoplexy (CPL) which involved multiple chromosomes...
December 15, 2018: Leukemia Research
Rolando García, Weina Chen, Prasad Koduru
Clinically and genomically, plasma cell myeloma (PCM) is a complex disease affecting the elderly population and has often had a poor prognosis. Karyotypic analysis of tumor cells is somewhat limited due to a low proliferative index coupled with a low frequency of tumor cells in clinical samples. Nevertheless, complex karyotypes with a multitude of numerical, balanced and unbalanced structural aberrations have been reported in these tumors. In this study we evaluated the karyotypes obtained in a single institution to identify recurring cytogenetic abnormalities...
December 2018: Cancer Genetics
Benoît Tessoulin, Agnès Moreau-Aubry, Géraldine Descamps, Patricia Gomez-Bougie, Sophie Maïga, Alban Gaignard, David Chiron, Emmanuelle Ménoret, Steven Le Gouill, Philippe Moreau, Martine Amiot, Catherine Pellat-Deceunynck
BACKGROUND: Human myeloma cell lines (HMCLs) are widely used for their representation of primary myeloma cells because they cover patient diversity, although not fully. Their genetic background is mostly undiscovered, and no comprehensive study has ever been conducted in order to reveal those details. METHODS: We performed whole-exon sequencing of 33 HMCLs, which were established over the last 50 years in 12 laboratories. Gene expression profiling and drug testing for the 33 HMCLs are also provided and correlated to exon-sequencing findings...
December 13, 2018: Journal of Hematology & Oncology
Susana Magadán Mompó, África González-Fernández
Due to the difficulties found when generating fully human monoclonal antibodies (mAbs) by the traditional method, several efforts have attempted to overcome these problems, with varying levels of success. One approach has been the development of transgenic mice carrying immunoglobulin (Ig) genes in germline configuration. The engineered mouse genome can undergo productive rearrangement in the B-cell population, with the generation of mouse B lymphocytes expressing human Ig (hIg) chains. To avoid the expression of mouse heavy or light chains, the endogenous mouse Ig (mIg) loci must be silenced by gene-targeting techniques...
2019: Methods in Molecular Biology
L Rasche, N Weinhold
BACKGROUND: Multiple myeloma (MM) is a hematologic malignancy characterized by monoclonal plasma cells infiltrating the bone marrow thereby causing anemia and lytic bone lesions. Despite significant improvement in overall survival, most MM patients inevitably, yet unpredictably, develop refractory disease and MM remains largely incurable. OBJECTIVE: This article describes the stages of progression and presents current insights into the pathogenesis of MM. MATERIAL AND METHODS: Discussion of basic conceptional works and most recent scientific publications...
January 2019: Der Internist
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