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Translational Diagnostics in Lymphoproliferative and Plasma Cell Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2018) | Viewed by 35528

Special Issue Editors

1. Royal Melbourne Hospital, Melbourne 3052, Australia
2. Peter MacCallum Cancer Centre, University of Melbourne, Parkville 3010, Australia
Interests: lymphoproliferative disorders; early drug development; clinical trials; targeting apoptosis
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Interests: haematology; leukaemia; aggressive lymphoma

Special Issue Information

Dear Colleagues,

Over the past five years, the genomes and transcriptomes of many types of lymphoproliferative disorders (LPDs) have been extensively characterized. We now have access to the mutational profile, gene expression signatures, and epigenomic data for most of the major subtypes of LPDs, and, through these data, we have a deepening understanding of their biology and pathogenesis. This understanding, in turn, is beginning to inform the selection of treatment in patients with these disorders in the clinic and identify mechanisms of resistance to conventional and novel agents. In order to translate these important findings into changes in patient care, these novel techniques and assays need to be implemented into the diagnostic environment.

This Special Issue will focus on original research and descriptions of the utilization of novel genomic technology in the diagnostic setting for LPDs and Plasma Cell Disorders (PCDs). This includes the use of next generation sequencing in the diagnostic laboratory, implementation of novel genomic technologies and techniques into diagnostic practice, validation of new genomic assays, description of illustrative cases and description of bioinformatic advances relevant to LPD and PCD diagnostics.

Prof. John F. Seymour
Dr. Piers A. Blombery
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • Next generation sequencing
  • Lymphoma
  • Molecular diagnostics
  • Lymphoproliferative disorders
  • RNA-seq
  • Gene expression profiling

Published Papers (7 papers)

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Review

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16 pages, 1719 KiB  
Review
Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies
by Wolfgang Willenbacher, Andreas Seeber, Normann Steiner, Ella Willenbacher, Zoran Gatalica, Jeff Swensen, Jeffery Kimbrough and Semir Vranic
Int. J. Mol. Sci. 2018, 19(7), 2087; https://doi.org/10.3390/ijms19072087 - 18 Jul 2018
Cited by 15 | Viewed by 4426
Abstract
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 [...] Read more.
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. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author’s own experiences/views. Full article
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24 pages, 1943 KiB  
Review
The Genomics and Molecular Biology of Natural Killer/T-Cell Lymphoma: Opportunities for Translation
by Sanjay De Mel, Gwyneth Shook-Ting Soon, Yingting Mok, Tae-Hoon Chung, Anand D. Jeyasekharan, Wee-Joo Chng and Siok-Bian Ng
Int. J. Mol. Sci. 2018, 19(7), 1931; https://doi.org/10.3390/ijms19071931 - 30 Jun 2018
Cited by 27 | Viewed by 8279
Abstract
Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is an aggressive malignancy with a poor prognosis. While the introduction of L-asparaginase in the treatment of this disease has significantly improved the prognosis, the outcome of patients relapsing after asparaginase-based chemotherapy, which occurs in up to [...] Read more.
Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is an aggressive malignancy with a poor prognosis. While the introduction of L-asparaginase in the treatment of this disease has significantly improved the prognosis, the outcome of patients relapsing after asparaginase-based chemotherapy, which occurs in up to 50% of patients with disseminated disease, remains dismal. There is hence an urgent need for effective targeted therapy especially in the relapsed/refractory setting. Gene expression profiling studies have provided new perspectives on the molecular biology, ontogeny and classification of ENKTL and further identified dysregulated signaling pathways such as Janus associated kinase (/Signal Transducer and activation of transcription (JAK/STAT), Platelet derived growth factor (PDGF), Aurora Kinase and NF-κB, which are under evaluation as therapeutic targets. Copy number analyses have highlighted potential tumor suppressor genes such as PR Domain Zinc Finger Protein 1 (PRDM1) and protein tyrosine phosphatase kappa (PTPRK) while next generation sequencing studies have identified recurrently mutated genes in pro-survival and anti-apoptotic pathways. The discovery of epigenetic dysregulation and aberrant microRNA activity has broadened our understanding of the biology of ENKTL. Importantly, immunotherapy via Programmed Cell Death -1 (PD-1) and Programmed Cell Death Ligand1 (PD-L1) checkpoint signaling inhibition is emerging as an attractive therapeutic strategy in ENKTL. Herein, we present an overview of the molecular biology and genomic landscape of ENKTL with a focus on the most promising translational opportunities. Full article
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19 pages, 266 KiB  
Review
Potential Clinical Application of Genomics in Multiple Myeloma
by Cinnie Yentia Soekojo, Sanjay De Mel, Melissa Ooi, Benedict Yan and Wee Joo Chng
Int. J. Mol. Sci. 2018, 19(6), 1721; https://doi.org/10.3390/ijms19061721 - 10 Jun 2018
Cited by 7 | Viewed by 4575
Abstract
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 [...] Read more.
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. Full article
17 pages, 2132 KiB  
Review
What Does This Mutation Mean? The Tools and Pitfalls of Variant Interpretation in Lymphoid Malignancies
by Yann Guillermin, Jonathan Lopez, Kaddour Chabane, Sandrine Hayette, Claire Bardel, Gilles Salles, Pierre Sujobert and Sarah Huet
Int. J. Mol. Sci. 2018, 19(4), 1251; https://doi.org/10.3390/ijms19041251 - 20 Apr 2018
Cited by 9 | Viewed by 5170
Abstract
High throughput sequencing (HTS) is increasingly important in determining cancer diagnoses, with subsequent prognostic and therapeutic implications. The biology of cancer is becoming increasingly deciphered and it is clear that therapy needs to be individually tailored. Whilst translational research plays an important role [...] Read more.
High throughput sequencing (HTS) is increasingly important in determining cancer diagnoses, with subsequent prognostic and therapeutic implications. The biology of cancer is becoming increasingly deciphered and it is clear that therapy needs to be individually tailored. Whilst translational research plays an important role in lymphoid malignancies, few guidelines exist to guide biologists and routine laboratories through this constantly evolving field. In this article, we review the challenges of interpreting HTS in lymphoid malignancies and provide a toolkit to interpret single nucleotide variants obtained from HTS. We define the pre-analytical issues such as sequencing DNA obtained from formalin-fixed and paraffin-embedded tissue (FFPE), the acquisition of germline DNA, or the bioinformatic pitfalls, the analytical issues encountered and how to manage them. We describe the main constitutional and cancer databases, their characteristics and limitations, with an emphasis on variant interpretation in lymphoid malignancies. Finally, we discuss the challenges of predictions that one can make using in silico or in vitro modelling, pharmacogenomic screening, and the limits of those prediction tools. This description of the current status in genomic interpretation highlights the need for new large databases and international collaboration in the lymphoma field. Full article
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Other

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13 pages, 2263 KiB  
Case Report
Circulating Tumour DNA Analysis for Tumour Genome Characterisation and Monitoring Disease Burden in Extramedullary Multiple Myeloma
by Sridurga Mithraprabhu, Shreerang Sirdesai, Maoshan Chen, Tiffany Khong and Andrew Spencer
Int. J. Mol. Sci. 2018, 19(7), 1858; https://doi.org/10.3390/ijms19071858 - 24 Jun 2018
Cited by 28 | Viewed by 4775
Abstract
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, [...] Read more.
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. DNA released into the blood by tumour cells (ctDNA) contains the predominant clones derived from the multiple disease foci. Blood-derived ctDNA can, therefore, provide a holistic illustration of the major drivers of disease progression. In this report, the utility of ctDNA, as an adjunct to currently available modalities in EM-MM, is presented for a patient with EM and oligosecretory (OS) disease. Whole exome sequencing of contemporaneously acquired tumour tissue and matched ctDNA samples revealed the presence of spatial and temporal genetic heterogeneity and the identification of pathways associated with drug resistance. Longitudinal monitoring of plasma samples revealed that ctDNA can be utilised to define the dynamic clonal evolution co-existent with disease progression and as an adjunct non-invasive marker of tumour burden. Full article
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8 pages, 6775 KiB  
Case Report
Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy
by Lucy C. Fox, Costas K. Yannakou, Georgina Ryland, Stephen Lade, Michael Dickinson, Belinda A. Campbell and Henry Miles Prince
Int. J. Mol. Sci. 2018, 19(6), 1758; https://doi.org/10.3390/ijms19061758 - 13 Jun 2018
Cited by 18 | Viewed by 3842
Abstract
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase [...] Read more.
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two CARD11-activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-κB) negative regulator, NFKBIE. In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance. Full article
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1372 KiB  
Case Report
The Diagnostic, Prognostic, and Therapeutic Utility of Molecular Testing in a Patient with Waldenstrom’s Macroglobulinemia
by Collin K. Chin, Connull Leslie, Carolyn S. Grove, Chris Van Vliet and Chan Yoon Cheah
Int. J. Mol. Sci. 2017, 18(10), 2038; https://doi.org/10.3390/ijms18102038 - 22 Sep 2017
Cited by 1 | Viewed by 3755
Abstract
The application of molecular genomics and our understanding of its clinical implications in the diagnosis, prognostication and treatment of lymphoproliferative disorders has rapidly evolved over the past few years. Of particular importance are indolent B-cell malignancies where tumour cell survival and proliferation are [...] Read more.
The application of molecular genomics and our understanding of its clinical implications in the diagnosis, prognostication and treatment of lymphoproliferative disorders has rapidly evolved over the past few years. Of particular importance are indolent B-cell malignancies where tumour cell survival and proliferation are commonly driven by mutations involving the B-cell receptor and downstream signalling pathways. In addition, the increasing number of novel therapies and targeted agents have provided clinicians with new therapeutic options with the aim of exploiting such mutations. In this case report, we highlight one such success story involving the diagnostic impact of the MYD88L265P mutation in Waldenstrom’s macroglobulinemia (WM), its prognostic implications and effect on choice of therapy in the era of novel therapies. Full article
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