173 results on '"Eileen M. Boyle"'
Search Results
2. Structural variants shape the genomic landscape and clinical outcome of multiple myeloma
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Cody Ashby, Eileen M. Boyle, Michael A. Bauer, Aneta Mikulasova, Christopher P. Wardell, Louis Williams, Ariel Siegel, Patrick Blaney, Marc Braunstein, David Kaminetsky, Jonathan Keats, Francesco Maura, Ola Landgren, Brian A. Walker, Faith E. Davies, and Gareth J. Morgan
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis.
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- 2022
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3. Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer
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Hussein Ghamlouch, Eileen M. Boyle, Patrick Blaney, Yubao Wang, Jinyoung Choi, Louis Williams, Michael Bauer, Daniel Auclair, Benedetto Bruno, Brian A. Walker, Faith E. Davies, and Gareth J. Morgan
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Multiple Myeloma ,PHF19 ,Polycomb Repressive Complex 2 ,PRC2 ,EZH2 ,Epigenetic ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.
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- 2021
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4. Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma
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Kylee H. Maclachlan, Even H. Rustad, Andriy Derkach, Binbin Zheng-Lin, Venkata Yellapantula, Benjamin Diamond, Malin Hultcrantz, Bachisio Ziccheddu, Eileen M. Boyle, Patrick Blaney, Niccolò Bolli, Yanming Zhang, Ahmet Dogan, Alexander M. Lesokhin, Gareth J. Morgan, Ola Landgren, and Francesco Maura
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Science - Abstract
Chromothripsis is associated with unfavourable outcomes in multiple myeloma (MM), but its detection usually requires whole genome sequencing. Here the authors develop an approach to detect chromothripsis in MM based on copy-number signatures that also works with whole exome sequencing data.
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- 2021
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5. A proof-of-concept study for the pathogenetic role of enhancer hypomethylation of MYBPHL in multiple myeloma
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Kwan Yeung Wong, Gareth J. Morgan, Eileen M. Boyle, Alfred Sze Lok Cheng, Kevin Yuk-Lap Yip, and Chor Sang Chim
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Medicine ,Science - Abstract
Abstract Enhancer DNA methylation and expression of MYBPHL was studied in multiple myeloma (MM). By bisulfite genomic sequencing, among the three CpGs inside the MYBPHL enhancer, CpG1 was significantly hypomethylated in MM cell lines (6.7–50.0%) than normal plasma cells (37.5–75.0%) (P = 0.007), which was negatively correlated with qPCR-measured MYBPHL expression. In RPMI-8226 and WL-2 cells, bearing the highest CpG1 methylation, 5-azadC caused enhancer demethylation and expression of MYBPHL. In primary samples, higher CpG1 methylation was associated with lower MYBPHL expression. By luciferase assay, luciferase activity was enhanced by MYBPHL enhancer compared with empty vector control, but reduced by site-directed mutagenesis of each CpG. RNA-seq data of newly diagnosed MM patients showed that MYBPHL expression was associated with t(11;14). MOLP-8 cells carrying t(11;14) express the highest levels of MYBPHL, and its knockdown reduced cellular proliferation and increased cell death. Herein, as a proof-of-concept, our data demonstrated that the MYBPHL enhancer, particularly CpG1, was hypomethylated and associated with increased MYBPHL expression in MM, which was implicated in myelomagenesis.
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- 2021
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6. The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma
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Eileen M. Boyle, Shayu Deshpande, Ruslana Tytarenko, Cody Ashby, Yan Wang, Michael A. Bauer, Sarah K. Johnson, Christopher P. Wardell, Sharmilan Thanendrarajan, Maurizio Zangari, Thierry Facon, Charles Dumontet, Bart Barlogie, Arnaldo Arbini, Even H. Rustad, Francesco Maura, Ola Landgren, Fenghuang Zhan, Frits van Rhee, Carolina Schinke, Faith E. Davies, Gareth J. Morgan, and Brian A. Walker
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Science - Abstract
Progression from asymptomatic smoldering multiple myeloma (SMM) to symptomatic Multiple Myeloma occurs at different rates in different patients. Here, the authors report fewer NRAS and FAM46C mutations and adverse translocations in SMM compared to MM, while KRAS mutations are associated with a shorter time to progression.
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- 2021
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7. Accelerated single cell seeding in relapsed multiple myeloma
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Heather J. Landau, Venkata Yellapantula, Benjamin T. Diamond, Even H. Rustad, Kylee H. Maclachlan, Gunes Gundem, Juan Medina-Martinez, Juan Arango Ossa, Max F. Levine, Yangyu Zhou, Rajya Kappagantula, Priscilla Baez, Marc Attiyeh, Alvin Makohon-Moore, Lance Zhang, Eileen M. Boyle, Cody Ashby, Patrick Blaney, Minal Patel, Yanming Zhang, Ahmet Dogan, David J. Chung, Sergio Giralt, Oscar B. Lahoud, Jonathan U. Peled, Michael Scordo, Gunjan Shah, Hani Hassoun, Neha S. Korde, Alexander M. Lesokhin, Sydney Lu, Sham Mailankody, Urvi Shah, Eric Smith, Malin L. Hultcrantz, Gary A. Ulaner, Frits van Rhee, Gareth J. Morgan, Ola Landgren, Elli Papaemmanuil, Christine Iacobuzio-Donahue, and Francesco Maura
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Science - Abstract
In multiple myeloma, disease progresses via seeding to different anatomic sites and clonal expansion. Here, utilising autopsy material, the authors show that systemic seeding accelerates at relapse following treatment.
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- 2020
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8. TarPan: an easily adaptable targeted sequencing panel viewer for research and clinical use
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Cody Ashby, Michael Rutherford, Michael A. Bauer, Erich A. Peterson, Yan Wang, Eileen M. Boyle, Christopher P. Wardell, and Brian A. Walker
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Cancer ,Visualization ,Somatic mutations ,Structural variants ,Copy number ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background The study of cancer genomics continually matures as the number of patient samples sequenced increases. As more data is generated, oncogenic drivers for specific cancer types are discovered along with their associated risks. This in turn leads to potential treatment strategies that pave the way to precision medicine. However, significant financial and analytical barriers make it infeasible to sequence the entire genome of every patient. In contrast, targeted sequencing panels give reliable information on relevant portions of the genome at a fiscally responsible cost. Therefore, we have created the Targeted Panel (TarPan) Viewer, a software tool, to investigate this type of data. Results TarPan Viewer helps investigators understand data from targeted sequencing data by displaying the information through a web browser interface. Through this interface, investigators can easily observe copy number changes, mutations, and structural events in cancer samples. The viewer runs in R Shiny with a robust SQLite backend and its input is generated from bioinformatic algorithms reliably described in the literature. Here we show the results from using TarPan Viewer on publicly available follicular lymphoma, breast cancer, and multiple myeloma data. In addition, we have tested and utilized the viewer internally, and this data has been used in high-impact peer-reviewed publications. Conclusions We have designed a flexible, simple to setup viewer that is easily adaptable to any type of cancer targeted sequencing, and has already proven its use in a research laboratory environment. Further, we believe with deeper sequencing and/or more targeted application it could be of use in the clinic in conjunction with an appropriate targeted sequencing panel as a cost-effective diagnostic test, especially in cancers such as acute leukemia or diffuse large B-cell lymphoma that require rapid interventions.
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- 2020
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9. Extracellular Vesicles as Biomarkers of Acute Graft-vs.-Host Disease After Haploidentical Stem Cell Transplantation and Post-Transplant Cyclophosphamide
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Giuseppe Lia, Clara Di Vito, Stefania Bruno, Marta Tapparo, Lucia Brunello, Armando Santoro, Jacopo Mariotti, Stefania Bramanti, Elisa Zaghi, Michela Calvi, Lorenzo Comba, Martina Fascì, Luisa Giaccone, Giovanni Camussi, Eileen M. Boyle, Luca Castagna, Andrea Evangelista, Domenico Mavilio, and Benedetto Bruno
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extracellular vesicles ,biomarkers ,acute GvHD ,haploidentical ,correlation ,miRNA ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Even with high-dose post-transplant cyclophosphamide (PT-Cy) which was initially introduced for graft-versus-host disease (GvHD) prevention in the setting of HLA-haploidentical transplantation, both acute and chronic GvHDs remain a major clinical challenge. Despite improvements in the understanding of the pathogenesis of both acute and chronic GvHDs, reliable biomarkers that predict their onset have yet to be identified. We recently studied the potential correlation between extracellular vesicles (EVs) and the onset of acute (a)GvHD in transplant recipients from related and unrelated donors. In the present study, we further investigated the role of the expression profile of membrane proteins and their microRNA (miRNA) cargo (miRNA100, miRNA155, and miRNA194) in predicting the onset of aGvHD in haploidentical transplant recipients with PT-Cy. Thirty-two consecutive patients were included. We evaluated the expression profile of EVs, by flow cytometry, and their miRNA cargo, by real-time PCR, at baseline, prior, and at different time points following transplant. Using logistic regression and Cox proportional hazard models, a significant association between expression profiles of antigens such as CD146, CD31, CD140a, CD120a, CD26, CD144, and CD30 on EVs, and their miRNA cargo with the onset of aGvHD was observed. Moreover, we also investigated a potential correlation between EV expression profile and cargo with plasma biomarkers (e.g., ST2, sTNFR1, and REG3a) that had been associated with aGVHD previously. This analysis showed that the combination of CD146, sTNFR1, and miR100 or miR194 strongly correlated with the onset of aGvHD (AUROC >0.975). A large prospective multicenter study is currently in progress to validate our findings.
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- 2022
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10. Differential RNA splicing as a potentially important driver mechanism in multiple myeloma
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Michael A. Bauer, Cody Ashby, Christopher Wardell, Eileen M. Boyle, Maria Ortiz, Erin Flynt, Anjan Thakurta, Gareth Morgan, and Brian A. Walker
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Disruption of the normal splicing patterns of RNA is a major factor in the pathogenesis of a number of diseases. Increasingly research has shown the strong influence that splicing patterns can have on cancer progression. Multiple Myeloma is a molecularly heterogeneous disease classified by the presence of key translocations, gene expression profiles and mutations but the splicing patterns in MM remains largely unexplored. We take a multifaceted approach to define the extent and impact of alternative splicing in MM. We look at the spliceosome component, SF3B1, with hotspot mutations (K700E and K666T/Q) shown to result in an increase in alternative splicing in other cancers. We discovered a number of differentially spliced genes in comparison of the SF3B1 mutant and wild type samples that included, MZB1, DYNLL1, TMEM14C and splicing related genes DHX9, CLASRP, and SNRPE. We identified a broader role for abnormal splicing showing clear differences in the extent of novel splice variants in the different translocation groups. We show that a high number of novel splice loci is associated with adverse survival and an ultra-high risk group. The enumeration of patterns of alternative splicing has the potential to refine MM classification and to aid in the risk stratification of patients.
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- 2020
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11. Acute myeloid leukemia synchronous with multiple myeloma successfully treated by azacytidine/lenalidomide and daratumumab without a decrease in myeloid clone size
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Celine Berthon, Morgane Nudel, Eileen M. Boyle, Laure Goursaud, Thomas Boyer, Alice Marceau, and Bruno Quesnel
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Myeloma ,AML ,CMML ,Azacytidine ,Lenalidomide ,Daratumumab ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Synchronous diagnosis of acute myeloid leukemia (AML) and symptomatic multiple myeloma (MM) is a rare situation that poses serious therapeutic difficulties. We report the case of a 68-year-old male which evolved simultaneously to symptomatic MM and AML. Both diseases first responded to treatment for 40 months after 7+3 induction and maintenance therapy of azacytidine + lenalidomide. MM relapsed first and was treated with azacytidine + daratumumab, which led an additional 15 months of progression-free survival. Little myeloid clonal size reduction over time was seen. This case shows that AML and MM can be effectively treated simultaneously using appropriate combinations.
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- 2020
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12. Author Correction: Accelerated single cell seeding in relapsed multiple myeloma
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Heather J. Landau, Venkata Yellapantula, Benjamin T. Diamond, Even H. Rustad, Kylee H. Maclachlan, Gunes Gundem, Juan Medina-Martinez, Juan Arango Ossa, Max F. Levine, Yangyu Zhou, Rajya Kappagantula, Priscilla Baez, Marc Attiyeh, Alvin Makohon-Moore, Lance Zhang, Eileen M. Boyle, Cody Ashby, Patrick Blaney, Minal Patel, Yanming Zhang, Ahmet Dogan, David J. Chung, Sergio Giralt, Oscar B. Lahoud, Jonathan U. Peled, Michael Scordo, Gunjan Shah, Hani Hassoun, Neha S. Korde, Alexander M. Lesokhin, Sydney Lu, Sham Mailankody, Urvi Shah, Eric Smith, Malin L. Hultcrantz, Gary A. Ulaner, Frits van Rhee, Gareth J. Morgan, Ola Landgren, Elli Papaemmanuil, Christine Iacobuzio-Donahue, and Francesco Maura
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Science - Abstract
A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-20978-y.
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- 2021
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13. The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma
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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, and Brian A. Walker
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Monoclonal gammopathy of undetermined significance is a pre-malignant 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 gene mutations, little is known about the molecular mechanism of malignant transformation. We performed whole exome sequencing together with comparative genomic hybridization plus single nucleotide polymorphism array analysis in 33 flow-cytometry-separated abnormal plasma cell samples from patients with monoclonal gammopathy of undetermined significance to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations and copy-number alterations were present in 97.0% and in 60.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in monoclonal gammopathy of undetermined significance than in myeloma (P
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- 2017
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14. Understanding the multiple biological aspects leading to myeloma
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Eileen M. Boyle, Faith E. Davies, Xavier Leleu, and Gareth J. Morgan
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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15. Tracking the Earliest Genomic Events in Multiple Myeloma Life-History
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Anthony Cirrincione, Bachisio Ziccheddu, Kylee H Maclachlan, Alexandra M. Poos, Monika Chojnacka, Benjamin Diamond, Eileen M Boyle, Patrick Blaney, Dylan Gagler, Yanming Zhang, Ahmet Dogan, Alexander M Lesokhin, Faith E. Davies, Neha Korde, Marc S Raab, Niels Weinhold, Saad Usmani, Gareth J. Morgan, Ola Landgren, and Francesco Maura
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
16. Fc-Mediated Antibody Effector Function, Inflammation Resolution and Oligoclonality on TCR Rearrangements Predict Sustained MRD Negativity in Newly Diagnosed Multiple Myeloma Treated with Immunotherapy Regimens
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Eileen M Boyle, Francesco Maura, David Coffey, Kylee H Maclachlan, Benjamin Diamond, Hussein Ghamlouch, Dylan Gagler, Patrick Blaney, Bachisio Ziccheddu, Yubao Wang, Emily Guzman, Avital Tenenbaum, Ariel Siegel, Xiaoyi Chen, Gaurav Varma, James E Hoffman, Dickran Kazandjian, Hani Hassoun, Sham Mailankody, Urvi A Shah, Carlyn Tan, Malin Hultcrantz, Michael Scordo, Gunjan L. Shah, Heather Landau, David J. Chung, Sergio A Giralt, Yanming Zhang, Ahmet Dogan, Alexander M Lesokhin, Dennis Verducci, Faith E Davies, Saad Usmani, Neha Korde, Ola Landgren, and Gareth J. Morgan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
17. Variability in Pattern of Mutational Signatures in Multiple Myeloma As a Function of Racial Origin
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Patrick Blaney, Eileen M Boyle, Kylee H Maclachlan, Louis S. Williams, Dylan Gagler, Parvathi Sudha, Alexandra M Poos, Yubao Wang, Hussein Ghamlouch, Avital Tenenbaum, Ariel Siegel, Xiaoyi Chen, Gaurav Varma, David Kaminetzsky, Marc Braunstein, David Coffey, Benjamin Diamond, Bachisio Ziccheddu, Dickran Kazandjian, Urvi A Shah, Elizabeth E. Brown, Elisabet E. Manasanch, Alexander M Lesokhin, Niels Weinhold, Brian A. Walker, Saad Usmani, Ola Landgren, Faith E Davies, Francesco Maura, and Gareth J. Morgan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
18. Data from Perspectives on the Risk-Stratified Treatment of Multiple Myeloma
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Gareth J. Morgan, Kenneth C. Anderson, Luciano J. Costa, Shaji K. Kumar, Brian A. Walker, Ajai Chari, Wee Joo Chng, Joseph Caers, Francesca Gay, C. Ola Landgren, Robert Z. Orlowski, Irene M. Ghobrial, Kathryn E. Morgan, Joseph R. Mikhael, Jonathan J. Keats, Katja Weisel, Martin F. Kaiser, P. Leif Bergsagel, A. Keith Stewart, Pieter Sonneveld, Sagar Lonial, Hearn Jay Cho, Daniel Auclair, Jill Corre, Eileen M. Boyle, Hermann Einsele, Jesus F. San-Miguel, Saad Z. Usmani, Charlotte Pawlyn, and Faith E. Davies
- Abstract
Summary:The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.
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- 2023
19. Supplementary Table from Perspectives on the Risk-Stratified Treatment of Multiple Myeloma
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Gareth J. Morgan, Kenneth C. Anderson, Luciano J. Costa, Shaji K. Kumar, Brian A. Walker, Ajai Chari, Wee Joo Chng, Joseph Caers, Francesca Gay, C. Ola Landgren, Robert Z. Orlowski, Irene M. Ghobrial, Kathryn E. Morgan, Joseph R. Mikhael, Jonathan J. Keats, Katja Weisel, Martin F. Kaiser, P. Leif Bergsagel, A. Keith Stewart, Pieter Sonneveld, Sagar Lonial, Hearn Jay Cho, Daniel Auclair, Jill Corre, Eileen M. Boyle, Hermann Einsele, Jesus F. San-Miguel, Saad Z. Usmani, Charlotte Pawlyn, and Faith E. Davies
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Supplementary Table from Perspectives on the Risk-Stratified Treatment of Multiple Myeloma
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- 2023
20. Supplementary material from The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma
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Gareth J. Morgan, Brian A. Walker, Faith E. Davies, Bart Barlogie, Graham H. Jackson, Walter M. Gregory, Roger G. Owen, Mark T. Drayson, Gordon Cook, John R. Jones, Eileen M. Boyle, David A. Cairns, Paula Z. Proszek, Nasrin M. Dahir, Dil B. Begum, David C. Johnson, Shweta S. Chavan, Alex Murison, Christopher P. Wardell, Lorenzo Melchor, Christoph Heuck, Martin F. Kaiser, and Charlotte Pawlyn
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Supplementary Tables: Supplementary table 1: Demographics of the 463 patients included in the Myeloma XI analysis Supplementary table 2: List of epigenetic modifier genes used to interrogate the list of mutations in the Myeloma XI dataset Supplementary table 3: Demographics of the 156 patients included in the UAMS dataset Supplementary table 4: List of epigenetic modifier genes sequenced in UAMS dataset Supplementary table 5: SIFT analysis of Histone 1 family gene mutations Supplementary table 6: Multivariate cox-regression model for overall survival in Myeloma XI patients Supplementary table 7: Percentage of patients with mutations in genes encoding epigenetic modifiers sequenced in both the MYXI and UAMS datasets (as shown in Supplementary table 4) - Supplementary Figures: Supplementary Figure 1: Epigenetic genes mutated in {greater than or equal to}5/463 patients (>1%) in Myeloma XI dataset - location of mutation with respect to protein functional domains Supplementary Figure 2: Translocation subgroup distribution by presence or absence of epigenetic modifier mutation in the Myeloma XI dataset Supplementary Figure 3: Survival curves for Histone 1 mutations in Myeloma XI dataset Supplementary Figure 4: A comparison of the variant allele frequency between the MyXI and UAMS mutations Supplementary Figure 5: The distribution of mutations in epigenetic modifiers in previously treated patients by GEP70 risk score Supplementary Figure 6: A comparison of the UAMS molecular subgroup distribution by presence of epigenetic modifier mutations in previously treated patients
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- 2023
21. Supplementary Data from BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma
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Brian A. Walker, Gareth J. Morgan, Faith E. Davies, Anjan Thakurta, Graham Jackson, David Cairns, Bart Barlogie, Frits van Rhee, Maurizio Zangari, Carolina D. Schinke, Sharmilan Thanendrarajan, Thierry Facon, Charles Dumontet, Michael A. Bauer, Christopher P. Wardell, Michael W. Rutherford, Sarah K. Johnson, Antje Hoering, Erin Flynt, Erming Tian, Jeffrey Sawyer, Adam Rosenthal, Yan Wang, Hongwei Wang, Shayu Deshpande, Ruslana G. Tytarenko, Cody Ashby, and Eileen M. Boyle
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Clean and unmarked supplemental data
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- 2023
22. Data from The Spectrum and Clinical Impact of Epigenetic Modifier Mutations in Myeloma
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Gareth J. Morgan, Brian A. Walker, Faith E. Davies, Bart Barlogie, Graham H. Jackson, Walter M. Gregory, Roger G. Owen, Mark T. Drayson, Gordon Cook, John R. Jones, Eileen M. Boyle, David A. Cairns, Paula Z. Proszek, Nasrin M. Dahir, Dil B. Begum, David C. Johnson, Shweta S. Chavan, Alex Murison, Christopher P. Wardell, Lorenzo Melchor, Christoph Heuck, Martin F. Kaiser, and Charlotte Pawlyn
- Abstract
Purpose: Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike other B-cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been reported previously. We sought to address this using the results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.Experimental Design: Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences (Little Rock, AR). We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.Results: In diagnostic myeloma patient samples, we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.Conclusions: Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. Clin Cancer Res; 22(23); 5783–94. ©2016 AACR.
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- 2023
23. Data from BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma
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Brian A. Walker, Gareth J. Morgan, Faith E. Davies, Anjan Thakurta, Graham Jackson, David Cairns, Bart Barlogie, Frits van Rhee, Maurizio Zangari, Carolina D. Schinke, Sharmilan Thanendrarajan, Thierry Facon, Charles Dumontet, Michael A. Bauer, Christopher P. Wardell, Michael W. Rutherford, Sarah K. Johnson, Antje Hoering, Erin Flynt, Erming Tian, Jeffrey Sawyer, Adam Rosenthal, Yan Wang, Hongwei Wang, Shayu Deshpande, Ruslana G. Tytarenko, Cody Ashby, and Eileen M. Boyle
- Abstract
Purpose:Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets.Experimental Design:We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials.Results:As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance.Conclusions:Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.
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- 2023
24. Clinical characteristics and outcome of 318 families with familial monoclonal gammopathy: A multicenter Intergroupe Francophone du Myélome study
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Charles Dumontet, Delphine Demangel, Perrine Galia, Lionel Karlin, Laurent Roche, Mathieu Fauvernier, Camille Golfier, Marie‐Charlotte Laude, Xavier Leleu, Philippe Rodon, Murielle Roussel, Isabelle Azaïs, Chantal Doyen, Borhane Slama, Salomon Manier, Olivier Decaux, Maroulio Pertesi, Marie Beaumont, Denis Caillot, Eileen M. Boyle, Manuel Cliquennois, Pascale Cony‐Makhoul, Anne‐Violaine Doncker, Véronique Dorvaux, Marie Odile Petillon, Jean Fontan, Bénédicte Hivert, Isabelle Leduc, Cécile Leyronnas, Margaret Macro, Michel Maigre, Clara Mariette, Philippe Mineur, Sophie Rigaudeau, Bruno Royer, Laure Vincent, James Mckay, Emeline Perrial, Laurent Garderet, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Fédération Française pour la Recherche contre le Myélome et les Gammapathies (FFRMG) Institut National Du Cancer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Service d'hématologie
- Subjects
Chromosome Aberrations ,MESH: Humans ,Paraproteinemias ,MESH: Multiple Myeloma ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Hematology ,Prognosis ,Monoclonal Gammopathy of Undetermined Significance ,MESH: Prognosis ,MESH: Paraproteinemias ,MESH: Child ,MESH: Monoclonal Gammopathy of Undetermined Significance ,Humans ,MESH: Chromosome Aberrations ,Child ,Multiple Myeloma - Abstract
International audience; Familial forms of monoclonal gammopathy, defined as multiple myeloma (MM) or Monoclonal Gammopathy of Undetermined Significance (MGUS), are relatively infrequent and most series reported in the literature describe a limited number of families. MM rarely occurs in a familial context. MGUS is observed much more commonly, which can in some cases evolve toward full-blown MM. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of MM, the pathogenesis of familial MM remains largely unexplained. In order to identify genetic factors predisposing to familial monoclonal gammopathy, the Intergroupe Francophone du Myélome identified 318 families with at least two confirmed cases of monoclonal gammopathy. There were 169 families with parent/child pairs and 164 families with cases in at least two siblings, compatible with an autosomal transmission. These familial cases were compared with sporadic cases who were matched for age at diagnosis, sex and immunoglobulin isotype, with 10 sporadic cases for each familial case. The gender distribution, age and immunoglobulin subtypes of familial cases were unremarkable in comparison to sporadic cases. With a median follow-up of 7.4 years after diagnosis, the percentage of MGUS cases having evolved to MM was 3%. The median overall survival of the 148 familial MM cases was longer than that of matched sporadic cases, with projected values of 7.6 and 16.1 years in patients older and younger than 65 years, respectively. These data suggest that familial cases of monoclonal gammopathy are similar to sporadic cases in terms of clinical presentation and carry a better prognosis.
- Published
- 2023
25. Impact of Etiological Cytogenetic Abnormalities on the Depth of Immunoparesis and Survival in Newly Diagnosed Multiple Myeloma
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Faith E. Davies, Jessica Caro, Gareth J. Morgan, David A Cairns, Tom Menzies, Jennifer L J Heaney, Graham Jackson, Mark T. Drayson, Charlotte Pawlyn, Eileen M Boyle, Martin Kaiser, Gordon Cook, Brian A Walker, and Roger G. Owen
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunoglobulins ,Disease ,Plasma cell ,Internal medicine ,medicine ,Humans ,Multiple myeloma ,Retrospective Studies ,Chromosome Aberrations ,business.industry ,Cytogenetics ,Immunosuppression ,Hematology ,Prognosis ,medicine.disease ,medicine.anatomical_structure ,Etiology ,Bone marrow ,Hyperdiploidy ,Multiple Myeloma ,business - Abstract
Microabstract Immunoparesis is associated with poor survival in myeloma (MM). We demonstrate that the etiological cytogenetic abnormality influences the degree and clinical impact of immunoparesis in newly diagnosed patients in a large clinical trial. As the depth of IgM immunoparesis impacts survival for hyperdiploid patients, this may be used to further risk-stratify this cytogenetic subgroup of patients for future clinical decisions. Introduction/Background Immunoparesis, or low polyclonal immunoglobulin levels, is commonly seen in multiple myeloma (MM) and is associated with poor clinical outcomes. MM can be divided into subgroups with distinct biology and outcomes based on etiological cytogenetic abnormalities. These include hyperdiploidy and translocations of t(11;14), t(4;14), t(14;16), and t(14;20), with the latter three associated with high-risk disease. We hypothesized that the different etiological cytogenetic abnormalities drive bone marrow microenvironmental changes, resulting in different degrees of immunoparesis and subgroup-dependent effects on clinical outcomes. Materials and Methods We performed a retrospective review of 985 newly diagnosed patients enrolled in the Myeloma IX and XI trials. Immunoglobulin levels, survival outcomes, and infection rates were evaluated for each cytogenetic subgroup. Results A significant proportion of patients with high-risk t(4;14), t(14;16), or t(14;20) had suppressed polyclonal immunoglobulins compared to standard-risk patients with hyperdiploidy or t(11;14). The clinical impact of immunoparesis depended on the cytogenetic subgroup, with the degree of IgM suppression effecting progression-free and overall survival only in the hyperdiploid subgroup. There was no significant difference in infection rates amongst the etiological subgroups. Conclusions These findings demonstrate that the etiological cytogenetic subgroup influences the degree and clinical impact of immunoparesis. This suggests that the underlying cytogenetic abnormality affects remodeling of the bone marrow plasma cell niche, resulting in suppressed normal plasma cell function and low immunoglobulin levels.
- Published
- 2022
26. Chromothripsis as a pathogenic driver of multiple myeloma
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Hussein Ghamlouch, Marc Braunstein, Yubao Wang, Ben Diamond, James H. Stoeckle, Louis Williams, David Kaminetzky, Faith E. Davies, Cody Ashby, Eileen M Boyle, Gareth J. Morgan, Michael A Bauer, Kylee H Maclachlan, Francesco Maura, Benedetto Bruno, Patrick Blaney, Even H. Rustad, Ola Landgren, and Brian A Walker
- Subjects
0301 basic medicine ,Pathogenesis ,Computational biology ,Disease ,Biology ,Chromoplexy ,Structural variation ,03 medical and health sciences ,0302 clinical medicine ,Templated insertions ,medicine ,Humans ,Multiple myeloma ,Cancer ,Whole genome sequencing ,Chromothripsis ,Whole Genome Sequencing ,Early disease ,Pathogenic factor ,Cell Biology ,Prognosis ,medicine.disease ,030104 developmental biology ,Multiple Myeloma ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.
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- 2022
27. Impact of rare structural variant events in newly diagnosed multiple myeloma
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Monika Chojnacka, Benjamin Diamond, Bachisio Ziccheddu, Even Rustad, Kylee Maclachlan, Marios Papadimitriou, Eileen M. Boyle, Patrick Blaney, Saad Usmani, Gareth Morgan, Ola Landgren, and Francesco Maura
- Subjects
Article - Abstract
Whole genome sequencing (WGS) of newly diagnosed multiple myeloma patients (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e. hotspots) and causing recurrent copy number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as “recurrent SVs”. More than half SVs were not involved in recurrent events. The significance of these “rare SVs” has not been previously examined. In this study, we utilize 752 WGS and 591 RNA-seq data from NDMM patients to determine the role of rare SVs in myeloma pathogenesis. 94% of patients harbored at least one rare SV event. Rare SVs showed an SV-class specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs. Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a driver role in myeloma pathogenesis.SIGNIFICANCECharacterization of multiple myeloma genome revealed that more than half structural variants are not involved in recurrent events. Here, we demonstrate that these rare SVs hold potential for myeloma pathogenesis through their gene expression impact. Rare SVs contribute to MM heterogeneity and have implications for development of individualized treatment.
- Published
- 2023
28. Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer
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Benedetto Bruno, Yubao Wang, Hussein Ghamlouch, Brian A Walker, Michael A Bauer, Faith E. Davies, Patrick Blaney, Louis Williams, Eileen M Boyle, Daniel Auclair, Jinyoung Choi, and Gareth J. Morgan
- Subjects
Cancer Research ,Cancer progression ,Review ,macromolecular substances ,EZH2 ,Epigenetic ,Multiple Myeloma ,PHF19 ,PRC2 ,Polycomb Repressive Complex 2 ,DNA-Binding Proteins ,Humans ,Survival Analysis ,Transcription Factors ,medicine ,Epigenetics ,Multiple myeloma ,RC254-282 ,biology ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Histone ,Oncology ,PHD finger ,Tumor progression ,Cancer research ,biology.protein - Abstract
Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02185-1.
- Published
- 2021
29. Patient experiences of referral practices and primary care physiotherapy for chronic nonspecific low back pain
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Eileen M Boyle, Kerrie Evans, Sonia Coates, Robyn E Fary, Kim Bennell, Michele Sterling, Trudy Rebbeck, and Darren J Beales
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Physical Therapy, Sports Therapy and Rehabilitation - Abstract
Low back pain (LBP) clinical practice guidelines recommend referral for patients with persistent LBP however discordance persists between recommended care and implementation in practice. Understanding patient experiences of referral practices and physiotherapy care could be important for optimizing LBP management in primary care settings.This study explored referral experiences of people with nonspecific LBP in Australian primary care and their knowledge and experience of physiotherapy.An interpretive descriptive qualitative framework was used with 17 participants interviewed from community-based physiotherapy practices.Four themes described the participants' experiences of referrals in primary care settings: 1) Referral practices ranged from formal to informal to non-existent; 2) Fragmented inter-and intra-professional LBP care management; 3) Patient perceived differences in the roles of physiotherapists and specialist physiotherapists; and 4) Patient nominated barriers and facilitators to optimal referral practices.Physiotherapists support people with LBP to improve strength and function, whereas the specialist physiotherapist's role was seen as more holistic. Referral pathways that align to clinical guideline recommendations for non-surgical management and treatment remain underdeveloped. Improved referral pathways to clinicians such as physiotherapists with additional credentialed skills and competence in musculoskeletal care could improve people's experiences of care and health outcomes.
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- 2022
30. The PANGEA model: catching the drift from precursor conditions to myeloma in individual patients
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Zoé Van de Wyngaert and Eileen M Boyle
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Hematology - Published
- 2023
31. Treatment with temozolomide and ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL)
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Nathalie Cambier, Guillaume Chanteau, Guillaume Escure, Remi Tilmont, Mathieu Wemeau, Jean Baptiste Bossard, Loïc Renaud, Julia Hieulle, Sarah Barbieux, Franck Morschhauser, Eileen M Boyle, Louis Terriou, Benjamin Carpentier, Hôpital Claude Huriez [Lille], CHU Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Saint Vincent de Paul de Lille, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Centre hospitalier [Valenciennes, Nord], Memorial Sloane Kettering Cancer Center [New York], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Groupe Hospitalier de l'Institut Catholique de Lille (GHICL)
- Subjects
Adult ,Male ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Best Overall Response ,Gastroenterology ,Unmet needs ,Central Nervous System Neoplasms ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Refractory ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Temozolomide ,Humans ,Medicine ,ComputingMilieux_MISCELLANEOUS ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Adenine ,Neoplasms, Second Primary ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Confidence interval ,3. Good health ,Lymphoma ,chemistry ,030220 oncology & carcinogenesis ,Charlson comorbidity index ,Ibrutinib ,Female ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Recurrence, Local ,business ,030215 immunology ,medicine.drug - Abstract
Despite recent therapeutic advances the outcome of elderly or frail patients with Recurrent/Refractory (R/R) Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL) is particularly dire. We retrospectively analyzed 22 immunocompetent adults with R/R PCNSL or SCNSL treated with both temozolomide and ibrutinib in five French centers, from June 2015 to January 2020. The median age at treatment initiation was 71 (range, 44 - 89 years). All patients had relapsed (n=6) or refractory (n=16) disease, after a median of two lines of therapy (range, 1-3). The median Charlson Comorbidity Index was 5 (range, 2-8). Patients received a median of 3.2 cycles (1-19 cycles). The best overall response rate was 55% (12/22) including three (13.6%) complete responses. After a median follow-up of 18.2 months (range, 5.1 - 61.7), the median progression-free survival (PFS) and overall survival (OS) were 5.3 months (95% confidence interval [CI]; 3.10 - ∞) and 8.9 months (95% CI; 5.2 - ∞) respectively. Among responders, the median PFS and OS were 11.7 months (95% CI; 7 - ∞) and 21.8 months (95% CI; 10 - ∞) respectively. Our data suggest temozolomide combined with ibrutinib displayed clinical activity with manageable side effects might be an option in these frail R/R CNS lymphomas in unmet need.
- Published
- 2021
32. From Bench to Bedside
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Faith E. Davies, Eileen M Boyle, and Gareth J. Morgan
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Cancer Research ,Biological studies ,Oncology ,medicine ,Genomics ,Context (language use) ,Identification (biology) ,Computational biology ,medicine.disease ,Multiple myeloma ,Bench to bedside ,Patient care - Abstract
The summation of 20 years of biological studies and the comprehensive analysis of more than 1000 multiple myeloma genomes with data linked to clinical outcome has enabled an increased understanding of the pathogenesis of multiple myeloma in the context of normal plasma cell biology. This novel data have facilitated the identification of prognostic markers and targets suitable for therapeutic manipulation. The challenge moving forward is to translate this genetic and biological information into the clinic to improve patient care. This review discusses the key data required to achieve this and provides a framework within which to explore the use of response-adapted, biologically targeted, molecularly targeted, and risk-stratified therapeutic approaches to improve the management of patients with multiple myeloma.
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- 2021
33. From little subclones grow mighty oaks
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Eileen M. Boyle and Faith E. Davies
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Oncology - Published
- 2023
34. Bartonellosis mimicking post-transplant lymphoproliferative diseases
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Marc Hazzan, Arnaud Lionet, C. Baillet, Guillaume Lassailly, Fanny Vuotto, Céline Dupré, Franck Morschhauser, Marie Frimat, Louis Terriou, and Eileen M Boyle
- Subjects
Transplantation ,medicine.medical_specialty ,Bartonellosis ,business.industry ,MEDLINE ,medicine.disease ,Kidney Transplantation ,Dermatology ,Lymphoproliferative Disorders ,Post transplant ,Nephrology ,Bartonella Infections ,Humans ,Medicine ,business - Published
- 2021
35. Structural Heterogeneity of Chromosome 1q Drives Outcome in Newly Diagnoses Myeloma
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Eileen M Boyle, Patrick Blaney, James Stoeckle, Yubao Wang, Hussein Ghamlouch, Avital Tenenbaum, Ariel Siegel, Xiaoyi Chen, Gaurav Varma, David Kaminetzsky, Marc Braunstein, Lydia Montes, Jill Corre, Even H Rustad, Ola Landgren, Francesco Maura, Benedetto Bruno, Aristotelis Tsirigos, Brian A. Walker, Faith E Davies, Dylan Gagler, and Gareth J. Morgan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
36. The Mutagenic Impact of Radiotherapy in Multiple Myeloma
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Benjamin Diamond, Alexandra M Poos, Bachisio Ziccheddu, Kylee H Maclachlan, Yanming Zhang, Saad Usmani, Eileen M Boyle, Faith E Davies, Gareth J. Morgan, Ola Landgren, Marc S Raab, Francesco Maura, and Niels Weinhold
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
37. Perspectives on the Risk-Stratified Treatment of Multiple Myeloma
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Faith E. Davies, Charlotte Pawlyn, Saad Z. Usmani, Jesus F. San-Miguel, Hermann Einsele, Eileen M. Boyle, Jill Corre, Daniel Auclair, Hearn Jay Cho, Sagar Lonial, Pieter Sonneveld, A. Keith Stewart, P. Leif Bergsagel, Martin F. Kaiser, Katja Weisel, Jonathan J. Keats, Joseph R. Mikhael, Kathryn E. Morgan, Irene M. Ghobrial, Robert Z. Orlowski, C. Ola Landgren, Francesca Gay, Joseph Caers, Wee Joo Chng, Ajai Chari, Brian A. Walker, Shaji K. Kumar, Luciano J. Costa, Kenneth C. Anderson, Gareth J. Morgan, and Hematology
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Humans ,General Medicine ,Multiple Myeloma ,Prognosis - Abstract
Summary: The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.
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- 2022
38. Monitoring treatment response and disease progression in myeloma with circulating cell‐free DNA
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Sharmilan Thanendrarajan, Shayu Deshpande, Frits van Rhee, Gareth J. Morgan, Ruslana Tytarenko, Faith E. Davies, Carolina Schinke, Brian A Walker, Eileen M Boyle, Yan Wang, Cody Ashby, Fenghuang Zhan, and Maurizio Zangari
- Subjects
Smoldering Multiple Myeloma ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,medicine.disease_cause ,Circulating Tumor DNA ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Bone Marrow ,Lactate dehydrogenase ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Medicine ,Alleles ,Multiple myeloma ,Chemotherapy ,business.industry ,Beta-2 microglobulin ,Hazard ratio ,Liquid Biopsy ,Computational Biology ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Hematology ,General Medicine ,Prognosis ,medicine.disease ,Circulating Cell-Free DNA ,Tumor Burden ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Concomitant ,Disease Progression ,ras Proteins ,KRAS ,Multiple Myeloma ,business ,030215 immunology - Abstract
Circulating cell-free DNA (cfDNA) has the potential to capture spatial genetic heterogeneity in myeloma (MM) patients. We assessed whether cfDNA levels vary according to risk status defined by the 70 gene expression profile (GEP70). cfDNA levels in 77 patients were significantly higher in the GEP70 high-risk (HR) group compared to the low-risk (LR) group and correlated weakly with clinical markers including lactate dehydrogenase, β2 -microglobulin, and ISS. Patients with high cfDNA levels were associated with a worse PFS (hazard ratio 6.4; 95% CI of ratio 1.9-22) and OS (hazard ratio 4.4; 95% CI of ratio 1.2-15.7). Circulating tumor DNA (ctDNA) was elevated in the HR group and ctDNA correlated strongly with GEP70 risk score (Spearman r = .69, P = .0027). cfDNA concentrations were significantly elevated between days 3-5 after chemotherapy before falling back to baseline levels. ctDNA in two patients showed a similar spike in levels between days 3 and 5 after chemotherapy with a concomitant increase in allele fraction of KRAS mutations. We assessed cfDNA levels in 25 patients with smoldering myeloma with serial samples and showed increased allele fraction of mutated KRAS at progression in cfDNA. Our study shows that cfDNA is a dynamic tool to capture genetic events in myeloma.
- Published
- 2020
39. Case Report: Two Cases of Cryptosporidiosis in Heavily Pretreated Patients With Myeloma
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Marie-Pierre Noel, Emilie Fréalle, Eileen M Boyle, Faith E. Davies, Charles Herbaux, Guillaume Escure, Hélène Demarquette, Alexandre Willaume, Thierry Facon, Jessica Caro, Gareth J. Morgan, Camille Cordier, Zoé Van de Wyngaert, Jordane Demonchy, Claire Bories, Karine Faure, and Serge Alfandari
- Subjects
Diarrhea ,Male ,Cancer Research ,Cryptosporidiosis ,Cryptosporidium ,03 medical and health sciences ,0302 clinical medicine ,Acquired immunodeficiency syndrome (AIDS) ,parasitic diseases ,Humans ,Medicine ,Multiple myeloma ,Immunodeficiency ,Antiparasitic Agents ,biology ,business.industry ,Disease Management ,Hematology ,Middle Aged ,Nitro Compounds ,medicine.disease ,biology.organism_classification ,Combined Modality Therapy ,Thiazoles ,Treatment Outcome ,Cryptosporidium parvum ,Oncology ,030220 oncology & carcinogenesis ,Parasitic disease ,Retreatment ,Immunology ,Female ,Disease Susceptibility ,Symptom Assessment ,medicine.symptom ,Stem cell ,Multiple Myeloma ,Tomography, X-Ray Computed ,business ,030215 immunology - Abstract
In Western countries, Cryptosporidium parvum infection is considered a rare opportunistic parasitic disease, most commonly seen in immunocompromised patients. Although most cases have been described in Acquired ImmunoDeficiency Syndrome (AIDS) patients, an increase of cases in other immunocompromised patients has been noted. We hereby describe the case of two patients from our institution in Northern France with heavily pre-treated multiple myeloma, both of whom underwent allogeneic stem cell transplants, who presented late Cryptosporidium infections while treated on novel agents. These cases illustrate novel examples of infection in multiple myeloma as survival improves and novel treatment approaches are being applied.
- Published
- 2021
40. A systematic scoping review of patient health outcomes and perceptions following management of low back pain via care pathways in primary health care
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Kerrie Evans, Robyn Fary, Kwangil Kang, Trudy Rebbeck, Eileen M. Boyle, and Darren Beales
- Subjects
medicine.medical_specialty ,Nursing (miscellaneous) ,business.industry ,media_common.quotation_subject ,Rehabilitation ,Primary health care ,Physical Therapy, Sports Therapy and Rehabilitation ,Primary care ,Health outcomes ,Low back pain ,Rheumatology ,Perception ,Family medicine ,Patient experience ,medicine ,Orthopedics and Sports Medicine ,Chiropractics ,medicine.symptom ,business ,media_common - Published
- 2020
41. Deep sequencing as an approach to understanding the complexity and improving the treatment of multiple myeloma
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Jessica Caro, Beatrice M. Razzo, Louis Williams, Eileen M Boyle, and Gareth J. Morgan
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Pharmacology ,Whole genome sequencing ,Plasma cell dyscrasia ,Computational biology ,Biology ,medicine.disease ,DNA sequencing ,Deep sequencing ,Drug Discovery ,Genetics ,medicine ,Molecular Medicine ,Exome sequencing ,Multiple myeloma - Abstract
Multiple myeloma (MM) is plasma cell dyscrasia with marked variability in its clinical presentation and outcome, both of which are dictated by its underlying genetics. Next-generation sequencing te...
- Published
- 2020
42. Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high-risk mutational patterns
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Gareth J. Morgan, Naveen Yarlagadda, Meera Mohan, Shayu Deshpande, Pingping Qu, Carolina Schinke, Maliha Khan, Katie R. Ryan, Bart Barlogie, Yan Wang, Antje Hoering, Eileen M Boyle, Maurizio Zangari, Brian A Walker, Sharmilan Thanendrarajan, Faith E. Davies, Cody Ashby, Samrat Roy Choudhury, Frits van Rhee, Christopher P. Wardell, and Valeriy V. Lyzogubov
- Subjects
Adult ,Male ,Chromosomal translocation ,Disease ,Biology ,lcsh:RC254-282 ,Article ,Translocation, Genetic ,Leukemia, Plasma Cell ,Mutation Rate ,Exome Sequencing ,medicine ,Cancer genomics ,Humans ,Multiple myeloma ,Aged ,Plasma cell leukemia ,Aged, 80 and over ,Cell adhesion molecule ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,Hematology ,Genomics ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Phenotype ,Gene expression profiling ,Oncology ,Mutation ,Cancer research ,Female ,Hyperdiploidy ,Transcriptome - Abstract
Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by the presence of ≥20% circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood and, given the rarity of the disease, are challenging to study. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype, we performed whole-exome sequencing and gene expression analysis in 23 and 41 patients with newly diagnosed pPCL, respectively. The results reveal an enrichment of complex structural changes and high-risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular, pPCL patients with traditional low-risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group. Furthermore, gene expression profiling showed upregulation of adverse risk modifiers in pPCL compared to non-pPCL MM, while adhesion molecules and extracellular matrix proteins became increasingly downregulated. In conclusion, this is one of the largest studies to dissect pPCL on a genomic and molecular level.
- Published
- 2020
43. BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma
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Graham Jackson, Eileen M Boyle, Antje Hoering, Shayu Deshpande, Sharmilan Thanendrarajan, Michael W. Rutherford, Brian A Walker, Adam Rosenthal, Sarah K. Johnson, David A Cairns, Maurizio Zangari, Gareth J. Morgan, Jeffrey R. Sawyer, Yan Wang, Christopher P. Wardell, Bart Barlogie, Ruslana Tytarenko, Frits van Rhee, Thierry Facon, Charles Dumontet, Hongwei Wang, Erming Tian, Cody Ashby, Anjan Thakurta, Carolina Schinke, Michael A Bauer, Faith E. Davies, and Erin Flynt
- Subjects
0301 basic medicine ,Oncology ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,medicine.medical_specialty ,business.industry ,Context (language use) ,Chromosomal translocation ,medicine.disease_cause ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,KRAS ,business ,Carcinogenesis ,neoplasms ,Gene ,V600E ,Multiple myeloma - Abstract
Purpose: Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. Experimental Design: We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials. Results: As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance. Conclusions: Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.
- Published
- 2020
44. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis
- Author
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Bertrand Arnulf, Aurore Perrot, Bruno Royer, Laurent Frenzel, David Lavergne, Frank Bridoux, Sylvie Chevret, Fabien Le Bras, Cyrille Touzeau, Giampaolo Merlini, Véronique Dorvaux, Murielle Roussel, Eileen M Boyle, Anne-Marie Stoppa, Margaret Macro, Arnaud Jaccard, Lionel Karlin, Giovanni Palladini, Antoine Huart, and Pierre Morel
- Subjects
medicine.medical_specialty ,business.industry ,Amyloidosis ,Immunology ,Daratumumab ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Clinical trial ,Interquartile range ,Internal medicine ,Severity of illness ,medicine ,Adverse effect ,business ,Multiple myeloma - Abstract
Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC
- Published
- 2020
45. TarPan: an easily adaptable targeted sequencing panel viewer for research and clinical use
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Michael A Bauer, Erich A. Peterson, Cody Ashby, Michael E. Rutherford, Eileen M Boyle, Yan Wang, Brian A Walker, and Christopher P. Wardell
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Computer science ,Interface (computing) ,Gene Dosage ,Genomics ,Breast Neoplasms ,Computational biology ,Web Browser ,lcsh:Computer applications to medicine. Medical informatics ,Biochemistry ,Genome ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,Somatic mutations ,Neoplasms ,Humans ,Precision Medicine ,Molecular Biology ,Lymphoma, Follicular ,lcsh:QH301-705.5 ,030304 developmental biology ,Cancer ,Visualization ,0303 health sciences ,Copy number ,Genome, Human ,Applied Mathematics ,Diagnostic test ,High-Throughput Nucleotide Sequencing ,Precision medicine ,Computer Science Applications ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Mutation ,lcsh:R858-859.7 ,Female ,DNA microarray ,Multiple Myeloma ,Structural variants ,Algorithms ,Software - Abstract
Background The study of cancer genomics continually matures as the number of patient samples sequenced increases. As more data is generated, oncogenic drivers for specific cancer types are discovered along with their associated risks. This in turn leads to potential treatment strategies that pave the way to precision medicine. However, significant financial and analytical barriers make it infeasible to sequence the entire genome of every patient. In contrast, targeted sequencing panels give reliable information on relevant portions of the genome at a fiscally responsible cost. Therefore, we have created the Targeted Panel (TarPan) Viewer, a software tool, to investigate this type of data. Results TarPan Viewer helps investigators understand data from targeted sequencing data by displaying the information through a web browser interface. Through this interface, investigators can easily observe copy number changes, mutations, and structural events in cancer samples. The viewer runs in R Shiny with a robust SQLite backend and its input is generated from bioinformatic algorithms reliably described in the literature. Here we show the results from using TarPan Viewer on publicly available follicular lymphoma, breast cancer, and multiple myeloma data. In addition, we have tested and utilized the viewer internally, and this data has been used in high-impact peer-reviewed publications. Conclusions We have designed a flexible, simple to setup viewer that is easily adaptable to any type of cancer targeted sequencing, and has already proven its use in a research laboratory environment. Further, we believe with deeper sequencing and/or more targeted application it could be of use in the clinic in conjunction with an appropriate targeted sequencing panel as a cost-effective diagnostic test, especially in cancers such as acute leukemia or diffuse large B-cell lymphoma that require rapid interventions.
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- 2020
46. Differential RNA splicing as a potentially important driver mechanism in multiple myeloma
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Brian A Walker, Gareth J. Morgan, Eileen M Boyle, Christopher P. Wardell, Cody Ashby, Michael A Bauer, Anjan Thakurta, Erin Flynt, and Maria Ortiz
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Spliceosome ,RNA Splicing ,Computational biology ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Humans ,splice ,Gene ,030304 developmental biology ,0303 health sciences ,Serine-Arginine Splicing Factors ,Alternative splicing ,Wild type ,RNA ,Hematology ,Phosphoproteins ,Alternative Splicing ,030220 oncology & carcinogenesis ,Mutation ,RNA splicing ,Spliceosomes ,RNA Splicing Factors ,Multiple Myeloma - Abstract
Disruption of the normal splicing patterns of RNA is a major factor in the pathogenesis of a number of diseases. Increasingly research has shown the strong influence that splicing patterns can have on cancer progression. Multiple Myeloma is a molecularly heterogeneous disease classified by the presence of key translocations, gene expression profiles and mutations but the splicing patterns in MM remains largely unexplored. We take a multifaceted approach to define the extent and impact of alternative splicing in MM. We look at the spliceosome component, SF3B1, with hotspot mutations (K700E and K666T/Q) shown to result in an increase in alternative splicing in other cancers. We discovered a number of differentially spliced genes in comparison of the SF3B1 mutant and wild type samples that included, MZB1, DYNLL1, TMEM14C and splicing related genes DHX9, CLASRP, and SNRPE. We identified a broader role for abnormal splicing showing clear differences in the extent of novel splice variants in the different translocation groups. We show that a high number of novel splice loci is associated with adverse survival and an ultra-high risk group. The enumeration of patterns of alternative splicing has the potential to refine MM classification and to aid in the risk stratification of patients.
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- 2020
47. Inflammation and infection in plasma cell disorders: how pathogens shape the fate of patients
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Jessica Caro, Marc Braunstein, Louis Williams, Benedetto Bruno, David Kaminetzky, Ariel Siegel, Beatrice Razzo, Serge Alfandari, Gareth J. Morgan, Faith E. Davies, and Eileen M. Boyle
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Innate immunity ,Preventive medicine ,Inflammation ,Cancer Research ,Plasma Cells ,Immunity ,Myeloma ,Hematology ,Review Article ,Adaptive Immunity ,Infections ,Immunity, Innate ,Oncology ,Animals ,Humans ,Multiple Myeloma ,Innate - Abstract
The role of infection and chronic inflammation in plasma cell disorders (PCD) has been well-described. Despite not being a diagnostic criterion, infection is a common complication of most PCD and represents a significant cause of morbidity and mortality in this population. As immune-based therapeutic agents are being increasingly used in multiple myeloma, it is important to recognize their impact on the epidemiology of infections and to identify preventive measures to improve outcomes. This review outlines the multiple factors attributed to the high infectious risk in PCD (e.g. the underlying disease status, patient age and comorbidities, and myeloma-directed treatment), with the aim of highlighting future prophylactic and preventive strategies that could be implemented in the clinic. Beyond this, infection and pathogens as an entity are believed to also influence disease biology from initiation to response to treatment and progression through a complex interplay involving pathogen exposure, chronic inflammation, and immune response. This review will outline both the direct and indirect role played by oncogenic pathogens in PCD, highlight the requirement for large-scale studies to decipher the precise implication of the microbiome and direct pathogens in the natural history of myeloma and its precursor disease states, and understand how, in turn, pathogens shape plasma cell biology.
- Published
- 2022
48. From Bench to Bedside: The Evolution of Genomics and Its Implications for the Current and Future Management of Multiple Myeloma
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Gareth J, Morgan, Eileen M, Boyle, and Faith E, Davies
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Humans ,Genomics ,Multiple Myeloma ,Forecasting - Abstract
The summation of 20 years of biological studies and the comprehensive analysis of more than 1000 multiple myeloma genomes with data linked to clinical outcome has enabled an increased understanding of the pathogenesis of multiple myeloma in the context of normal plasma cell biology. This novel data have facilitated the identification of prognostic markers and targets suitable for therapeutic manipulation. The challenge moving forward is to translate this genetic and biological information into the clinic to improve patient care. This review discusses the key data required to achieve this and provides a framework within which to explore the use of response-adapted, biologically targeted, molecularly targeted, and risk-stratified therapeutic approaches to improve the management of patients with multiple myeloma.
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- 2021
49. High-risk transcriptional profiles in multiple myeloma are an acquired feature that can occur in any subtype and more frequently with each subsequent relapse
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Faith E. Davies, Brian A Walker, Antje Hoering, Philip Farmer, Bart Barlogie, Frits van Rhee, Sharmilan Thanendrarajan, Carolina Schinke, Yan Wang, Adam Z. Rosenthal, Gareth J. Morgan, Eileen M Boyle, Sarah K. Johnson, Christopher P. Wardell, Michael A Bauer, Cody Ashby, Maurizio Zangari, and Michael E. Rutherford
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Transcriptional Activation ,Subsequent Relapse ,Gene Expression Profiling ,Plasma Cells ,Remission Induction ,Hematology ,Biology ,medicine.disease ,Feature (computer vision) ,Recurrence ,Risk Factors ,medicine ,Cancer research ,Humans ,Syndecan-1 ,Neoplasm Recurrence, Local ,Precision Medicine ,Multiple Myeloma ,Multiple myeloma ,Cell Proliferation - Published
- 2021
50. Plasma cells expression from smouldering myeloma to myeloma reveals the importance of the PRC2 complex, cell cycle progression, and the divergent evolutionary pathways within the different molecular subgroups
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Sarah K. Johnson, Faith E. Davies, Frits van Rhee, Adam Z. Rosenthal, Eileen M Boyle, Carolina Schinke, Sharmilan Thanendrarajan, Madhav V. Dhodapkar, Antje Hoering, Hussein Ghamlouch, Christopher P. Wardell, Brian A Walker, Bart Barlogie, Cody Ashby, Gareth J. Morgan, Yan Wang, Michael E. Rutherford, Maurizio Zangari, Phillip Farmer, Yubao Wang, and Michael A Bauer
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Smoldering Multiple Myeloma ,Cancer Research ,Plasma Cells ,Disease ,Biology ,Pathogenesis ,Evolution, Molecular ,Gene expression ,medicine ,Biomarkers, Tumor ,Humans ,Gene ,Multiple myeloma ,Gene Expression Profiling ,EZH2 ,Cell Cycle ,Polycomb Repressive Complex 2 ,Hematology ,medicine.disease ,Prognosis ,Gene expression profiling ,Oncology ,Cancer research ,Smouldering myeloma ,Disease Progression ,Multiple Myeloma ,Signal Transduction - Abstract
Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.
- Published
- 2021
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