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Myeloma genomics

Wolfgang Willenbacher, Andreas Seeber, Normann Steiner, Ella Willenbacher, Zoran Gatalica, Jeff Swensen, Jeffery Kimbrough, Semir Vranic
Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients' survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients...
July 18, 2018: International Journal of Molecular Sciences
Susu Han, Tao Huang, Wen Li, Shanshan Liu, Wei Yang, Qi Shi, Hongjia Li, Jianlin Ren, Fenggang Hou
BACKGROUND/AIMS: Although some studies showed that HIF-2α expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2α expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2α expression in CRC. METHODS: Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets...
July 18, 2018: Cellular Physiology and Biochemistry
Martin Bommer, Miriam Kull, Veronica Teleanu, Phyllis Schwarzwälder, Manuela Feuring-Buske, Jan Kroenke, Donald Bunjes, Christian Langer
INTRODUCTION: Involvement of the central nervous system in patients with multiple myeloma is a rare event. We evaluated the diagnostic workup and prognosis of patients with leptomeningeal myelomatosis (LMM). METHODS: Between April 2005 and April 2016, we identified 16 cases with LMM. The involvement was diagnosed by magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) cytology as well as flow cytometry. Fluorescence in situ hybridization (FISH) was used in 8/16 cases...
July 11, 2018: Acta Haematologica
Yen-Chien Lee, Chung-Cheng Hsieh, Yen-Ling Lee, Chung-Yi Li
Molecular markers are important in guiding treatment and predicting outcome in the genomic era. Meta-analysis of molecular markers in myelofibrosis through a search of PubMed and Medline through October 31, 2017 was performed. Markers with more than 3 studies that compared overall survival (OS) and leukemia-free survival (LFS) were analyzed. A total of 16 studies were included. Hazard ratios (HRs) for OS were as follows: IDH 2.65 (95% confidence interval [CI], 1.66-4.21), SRSF2 2.12 (95% CI, 1.18-3.79), high-risk myeloma 2...
June 8, 2018: Clinical Lymphoma, Myeloma & Leukemia
Brian A Walker, Konstantinos Mavrommatis, Christopher P Wardell, T Cody Ashby, Michael Bauer, Faith Davies, Adam Rosenthal, Hongwei Wang, Pingping Qu, Antje Hoering, Mehmet Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Zhinuan Yu, Zhihong Yang, Dan Rozelle, John Obenauer, Matthew Trotter, Daniel Auclair, Jonathan Keats, Niccolo Bolli, Mariateresa Fulciniti, Raphael Szalat, Phillipe Moreau, Brian Durie, A Keith Stewart, Hartmut Goldschmidt, Marc S Raab, Hermann Einsele, Pieter Sonneveld, Jesus San Miguel, Sagar Lonial, Graham H Jackson, Kenneth C Anderson, Herve Avet-Loiseau, Nikhil Munshi, Anjan Thakurta, Gareth Morgan
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior...
July 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Yanira Ruiz-Heredia, Beatriz Sànchez-Vega, Esther Onecha, Santiago Barrio, Rafael Alonso, Jose Carlos Martínez-Ávila, Isabel Cuenca, Xabier Agirre, Esteban Braggio, Miguel-T Hernández, Rafael Martínez, Laura Rosiñol, Norma Gutierrez, Marisa Martin-Ramos, Enrique M Ocio, María Asunción Echeveste, Jaime Pérez de Oteyza, Albert Oriol, Joan Bargay, Mercedes Gironella, Rosa Ayala, Joan Bladé, María-Victoria Mateos, Klaus M Kortum, Keith Stewart, Ramón García-Sanz, Jesús San Miguel, Juan José Lahuerta, Joaquín Martinez-Lopez
Next-generation sequencing has substantially improved our understanding of the genomic landscape of multiple myeloma; however, the application of this technology has been confined mostly to research studies. Here, we report on a customized panel to characterize the mutational profile of 79 newly diagnosed patients with multiple myeloma, older than 65 years and who were not transplant candidates, applying the highest read depth to date that has been used for equivalent studies in multiple myeloma. Overall, we identified 53 genes mutated in 85% of patients, including KRAS, NRAS, BRAF, DIS3 and TP53, and found a complex subclonal structure...
June 28, 2018: Haematologica
Ajinkya Patil, Mark Manzano, Eva Gottwein
Primary effusion lymphoma (PEL) is an aggressive cancer with few treatment options. The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide have recently been shown to kill PEL cell lines and lenalidomide is in clinical trials against PEL. IMiDs bind to the CRL4CRBN E3 ubiquitin ligase complex, leading to the acquisition of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), casein kinase 1 alpha (CK1α) and zinc finger protein 91 (ZFP91) as neosubstrates. IMiDs are effective against multiple myeloma, due to degradation of IKZF1 and IKZF3 and the consequent loss of interferon regulatory factor 4 (IRF4) and MYC expression...
June 28, 2018: Blood
Aurelian Udristioiu, Delia Nica-Badea
In the past few years has used thetechnique for analyzing deletions of genes, its rearrangements, cross-reactivity or multiplications in human genome affected of genetic diseases. Was proved that, the best techniques in the investigation of malignant lymphocytes are the Flow Cytometry, Elisa, ICT and Fluorescence in situ hybridization (FISH). Last method, FISH is used as an alternative to chromosomal banding, a conventional application in molecular medicine and can detect the chromosomal rearrangements and complexes of different genes in malignant diseases, like chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia, (ALL), or multiple myeloma (MM)...
June 23, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Mingyue Shi, Xiaoyan Dong, Lei Huo, Xiaobin Wei, Fang Wang, Kai Sun
Hematological malignancies (HM) are a heterogeneous group of life-threatening hematological diseases. The heterogeneity and clonal evolution of HM subpopulations are the main obstacles for precise diagnoses, risk stratification, and even targeted therapies. Standard bulk-sample genomic examinations average total mutations from multiple subpopulations and conceal the clonal diversity that may play a significant role in HM progression. Therefore, the development of novel methods that detect intra-tumor heterogeneity is critical for the discovery of novel potential therapeutic targets...
2018: Advances in Experimental Medicine and Biology
Sridurga Mithraprabhu, Shreerang Sirdesai, Maoshan Chen, Tiffany Khong, Andrew Spencer
Mutational characterisation in extramedullary multiple myeloma (EM-MM) patients is challenging due to inaccessible EM plasmacytomas, unsafe nature of multiple biopsies and the spatial and temporal genomic heterogeneity apparent in MM (Graphical abstract). Conventional monitoring of disease burden is through serum markers and PET-CT, however these modalities are sometimes inadequate (serum markers), not performed in a timely manner (PET-CT) and uninformative for identifying mutations driving disease progression...
June 24, 2018: International Journal of Molecular Sciences
Cinnie Yentia Soekojo, Sanjay de Mel, Melissa Ooi, Benedict Yan, Wee Joo Chng
Multiple myeloma is a heterogeneous disease with different characteristics, and genetic aberrations play important roles in this heterogeneity. Studies have shown that these genetic aberrations are crucial in prognostication and response assessment; recent efforts have focused on their possible therapeutic implications. Despite many emerging studies being published, the best way to incorporate these results into clinical practice remains unclear. In this review paper we describe the different genomic techniques available, including the latest advancements, and discuss the potential clinical application of genomics in multiple myeloma...
June 10, 2018: International Journal of Molecular Sciences
Brian A Walker, Konstantinos Mavrommatis, Christopher P Wardell, T Cody Ashby, Michael Bauer, Faith E Davies, Adam Rosenthal, Hongwei Wang, Pingping Qu, Antje Hoering, Mehmet Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Zhinuan Yu, Zhihong Yang, Dan Rozelle, John Obenauer, Matthew Trotter, Daniel Auclair, Jonathan Keats, Niccolo Bolli, Mariateresa Fulciniti, Raphael Szalat, Philippe Moreau, Brian Durie, A Keith Stewart, Hartmut Goldschmidt, Marc S Raab, Hermann Einsele, Pieter Sonneveld, Jesus San Miguel, Sagar Lonial, Graham H Jackson, Kenneth C Anderson, Herve Avet-Loiseau, Nikhil Munshi, Anjan Thakurta, Gareth J Morgan
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1,273 newly diagnosed patients with multiple myeloma we identify 63 driver genes, some of which are novel including IDH1 , IDH2 , HUWE1 , KLHL6 , and PTPN11 Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure...
June 8, 2018: Blood
Ichiro Hanamura, Shinsuke Iida
Proteasome inhibitors and immunomodulatory drugs have substantially improved the clinical outcomes in patients with multiple myeloma (MM) since 2000. In 2015, the new monoclonal antibodies, daratumumab and elotuzumab, were approved for treating relapsed and/or refractory MM (RRMM). Furthermore, venetoclax, a selective BCL-2 inhibitor, and chimeric antigen receptor (CAR) T-cell therapy that work against B-cell maturation antigen (BCMA) have reportedly shown great efficacy in phase 1 studies. The efficacy of venetoclax has been observed in RRMM with t (11;14) and higher BCL-2/BCL-XL expression...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Maaike V J Braham, Monique C Minnema, Tineke Aarts, Zsolt Sebestyen, Trudy Straetemans, Anna Vyborova, Jurgen Kuball, F Cumhur Öner, Catherine Robin, Jacqueline Alblas
Bone marrow niches support multiple myeloma, providing signals and cell-cell interactions essential for disease progression. A 3D bone marrow niche model was developed, in which supportive multipotent mesenchymal stromal cells and their osteogenic derivatives were co-cultured with endothelial progenitor cells. These co-cultured cells formed networks within the 3D culture, facilitating the survival and proliferation of primary CD138+ myeloma cells for up to 28 days. During this culture, no genetic drift was observed within the genomic profile of the primary myeloma cells, indicating a stable outgrowth of the cultured CD138+ population...
2018: Oncoimmunology
Samrat Roy Choudhury, Brian A Walker
Reduced representation bisulfite sequencing (RRBS) is one of the most comprehensive yet economic ways of mapping whole genome DNA-methylation. Here, we have substantially modified the RRBS protocol by combining end-repair and A-tailing steps, and by introducing a bead-based method for rapid and easy size selection of the library molecules. The method has been optimized for myeloma clinical samples, where the input DNA concentration can be as low as 100 ng. The method developed can be accomplished in 3 days, including the initial overnight MspI enzyme digestion...
2018: Methods in Molecular Biology
Sridurga Mithraprabhu, Andrew Spencer
Circulating tumor DNA (ctDNA) analysis is currently gaining momentum as an innovative methodology for characterizing the tumor genome and monitoring therapeutic efficacy in the multifocal, genetically and spatially heterogeneous plasma cell malignancy, multiple myeloma (MM). Circulating cell-free DNA (cfDNA), which consists of a combination of DNA derived from both tumor and normal cells, is present in extracellular bodily fluids. The presence of ctDNA within this admixture has been demonstrated recently in MM...
2018: Methods in Molecular Biology
Santiago Barrio, Matteo DáVia, Laura Bruins, Thorsten Stühmer, Torsten Steinbrunn, Max Bittrich, Hermann Einsele, Alexander Keith Stewart, Esteban Braggio, Klaus Martin Kortüm
Over the past 10 years next generation sequencing (NGS) approaches deciphered a large number of genomes from a wide variety of tumor types. However, despite most relevant findings, this technology has not yet been implemented into standard diagnostic workflows. Broad access to NGS technology is still limited, sequencing/analysis times exceed clinically relevant timeframes and despite huge cuts, costs remain significant. We proposed a custom-tailored gene panel, which focuses on a selected number of relevant genes and developed a clinically oriented NGS targeted sequencing approach for the molecular characterization of Multiple Myeloma (MM) tumors, allowing the description of the tumor genetic heterogeneity and its changes under selective pressure of antitumor therapy, in a more cost effective and faster turnaround timeframe...
2018: Methods in Molecular Biology
Brian A Walker
Multiple myeloma is a malignancy of terminally differentiated plasma cells in the bone marrow. These plasma cells produce high levels of immunoglobulin which cause end-organ damage. Rearrangements within the immunoglobulin loci are a physiological part of B cell development, but these DNA level double-strand breaks may result in interchromosomal translocations. There are five main translocations involving the Ig loci: t(4;14) 12%, t(6;14) 1%, t(11;14) 15%, t(14;16) 3%, and t(14;20) 2%. These are primary events, found in all cells within the tumor clone and are associated with different prognosis...
2018: Methods in Molecular Biology
Erming Tian
The application of fluorescence in situ hybridization (FISH) technology in diagnosis and molecular classification of cancer-risk has become an essential tool in the proceeding of personalized therapy. In multiple myeloma, the precise FISH detection of numerical and structural genetic aberrations can be carried out on metaphase chromosome spreads, interphase nuclei, and formalin fixed paraffin-embedded (FFPE) tissues. To dissect highly complex cancer genomes, a broad variety of novel DNA probes, which outpace supplies from commercial resources on the market, are also crucial to the advanced translational researches...
2018: Methods in Molecular Biology
Niccolo Bolli, Giulia Biancon, Matahi Moarii, Silvia Gimondi, Yilong Li, Chiara de Philippis, Francesco Maura, Vijitha Sathiaseelan, Yu-Tzu Tai, Laura Mudie, Sarah O'Meara, Keiran Raine, Jon W Teague, Adam P Butler, Cristiana Carniti, Moritz Gerstung, Tina Bagratuni, Efstathios Kastritis, Meletios Dimopoulos, Paolo Corradini, Kenneth C Anderson, Philippe Moreau, Stephane Minvielle, Peter J Campbell, Elli Papaemmanuil, Herve Avet-Loiseau, Nikhil C Munshi
In multiple myeloma, next-generation sequencing (NGS) has expanded our knowledge of genomic lesions, and highlighted a dynamic and heterogeneous composition of the tumor. Here we used NGS to characterize the genomic landscape of 418 multiple myeloma cases at diagnosis and correlate this with prognosis and classification. Translocations and copy number abnormalities (CNAs) had a preponderant contribution over gene mutations in defining the genotype and prognosis of each case. Known and novel independent prognostic markers were identified in our cohort of proteasome inhibitor and immunomodulatory drug-treated patients with long follow-up, including events with context-specific prognostic value, such as deletions of the PRDM1 gene...
May 22, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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