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A Comprehensive Review of the Genomics of Multiple Myeloma: Evolutionary Trajectories, Gene Expression Profiling, and Emerging Therapeutics

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A Comprehensive Review of the Genomics of Multiple Myeloma: Evolutionary Trajectories, Gene Expression Profiling, and Emerging Therapeutics cells Review A Comprehensive Review of the Genomics of Multiple Myeloma: Evolutionary Trajectories, Gene Expression Profiling, and Emerging Therapeutics Hassan Awada 1,†, Bicky Thapa 2,† , Hussein Awada 1,† , Jing Dong 2, Carmelo Gurnari 1 , Parameswaran Hari 2 and Binod Dhakal 2,* 1 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44106, USA; [email protected] (H.A.); [email protected] (H.A.); [email protected] (C.G.) 2 Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; [email protected] (B.T.); [email protected] (J.D.); [email protected] (P.H.) * Correspondence: [email protected] † These authors contributed equally and are co-first authors. Abstract: Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant monoclonal plasma cells in the bone marrow. It develops through a series of premalignant plasma cell dyscrasia stages, most notable of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS). Significant advances have been achieved in uncovering the genomic aberrancies underlying the pathogenesis of MGUS-MM. In this review, we discuss in-depth the genomic evolution of MM and focus on the prognostic implications of the accompanied molecular and cytogenetic Citation: Awada, H.; Thapa, B.; Awada, H.; Dong, J.; Gurnari, C.; aberrations. We also dive into the latest investigatory techniques used for the diagnoses and risk Hari, P.; Dhakal, B. A Comprehensive stratification of MM patients. Review of the Genomics of Multiple Myeloma: Evolutionary Trajectories, Keywords: multiple myeloma; plasma cell dyscrasia; genomics; risk stratification; prognosis Gene Expression Profiling, and Emerging Therapeutics. Cells 2021, 10, 1961. https://doi.org/10.3390/ cells10081961 1. Introduction Multiple myeloma (MM), is a malignant clonal proliferation of plasma cells compro- Academic Editor: Alexander mising 1.8% of all new cancer cases in the U.S. based on the Surveillance, Epidemiology, E. Kalyuzhny and End Results Program (SEER) cancer database [1]. Data from randomized clinical trials revealed an overall five-year survival rate of about 54% and a median overall sur- Received: 28 June 2021 vival of approximately six years [2]. Most recently, a study on long-term outcomes in Accepted: 30 July 2021 Published: 2 August 2021 MM after autologous stem cell transplantation revealed better overall survival in patients treated in 2014 or after as compared to 1997 or before [3]. This significant difference in Publisher’s Note: MDPI stays neutral outcomes derives from the substantial progress made in the understanding of disease with regard to jurisdictional claims in pathobiology and the introduction of novel therapeutics [4,5]; yet prognosis remains poor, published maps and institutional affil- especially in genetically defined high-risk subgroups [6]. MM is a heterogeneous disease iations. characterized by the acquisition of complex genetic changes during disease evolution from the premalignant condition monoclonal gammopathy of undetermined significance (MGUS) [7] and smoldering MM (SMM) [8]. Seminal studies provided crucial information about the complex evolutionary process in MM patients and changes in genomics of clonal architecture as the disease progresses [9–11]. In clinical practice, conventional karyotyping Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. and interphase fluorescence in situ hybridization (FISH) from bone marrow samples are This article is an open access article utilized to classify genomic risk and identify patients with high-risk abnormalities [8]. distributed under the terms and Recently, extensive studies of MM genomics have led to an improved understanding of the conditions of the Creative Commons molecular biology of MM. This resulted in new molecular classifications of MM subtypes, Attribution (CC BY) license (https:// that have been proposed using gene expression profiling, and the identification of genes creativecommons.org/licenses/by/ involved in the disease process [12,13]. Here, we summarize the current knowledge on the 4.0/). complex genomic landscape and pathophysiological mechanisms of MM. Cells 2021, 10, 1961. https://doi.org/10.3390/cells10081961 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 16 expression profiling, and the identification of genes involved in the disease process [12,13]. Here, we summarize the current knowledge on the complex genomic landscape and pathophysiological mechanisms of MM. Cells 2021, 10, 1961 2. Genetic and Cytogenetic Abnormalities: A Long Way from MGUS to MM 2 of 15 Progression The genetic complexity of MM underlies a progressive, multistep process through which2. Genetic the continuous and Cytogenetic accumulation Abnormalities: of genetic Aaberrancies Long Way drives from MGUSmonoclonal to MM plasma cells towardsProgression malignancy [14]. These aberrancies are generally classified as either primary or secondaryThe genetic(Figure complexity 1). Primary of MM aberrancie underliess ainitiate progressive, the process multistep of process plasma through cell immortalizationwhich the continuous and its accumulation consequent of commitment genetic aberrancies to the drivesMM monoclonaldisease pathway plasma [15] cells. Whethertowards its malignancy progress [eventually14]. These aberranciesleads to MM are or generally halts/remains classified at an as eitherearlier primary phase is or dependentsecondary on (Figure the secondary1). Primary aberrancies aberrancies which initiate further the modulate process disease of plasma progression cell immortal- [15]. Itization is now andknown its consequentthat MM, in commitmentalmost all patients, to the evolves MM disease from pathwaya premalignant [15]. Whether precursor its stage,progress MGUS, eventually which leadsis characterized to MM or halts/remains by monoclonal at anplasma earlier cells phase of islimited dependent malignant on the potential.secondary Hence, aberrancies to fully which understand further the modulate genetic disease foundations progression of the [pathophysiology15]. It is now known of MM,that we MM, must in almost also consider all patients, the pathogenesis evolves from of a premalignantMGUS, its direct precursor precursor. stage, Several MGUS, studieswhich investigated is characterized the bygenomic monoclonal changes plasma occurring cells at of the limited stage malignant of MGUSpotential. [16,17]. Hence, to fully understand the genetic foundations of the pathophysiology of MM, we must also consider the pathogenesis of MGUS, its direct precursor. Several studies investigated the genomic changes occurring at the stage of MGUS [16,17]. Figure 1. The sequence of genomic events in the molecular pathogenesis of multiple myeloma. Figure 1. The sequence of genomic events in the molecular pathogenesis of multiple myeloma. Plasma cells are terminally differentiated B cells, which in physiologic conditions are incapablePlasma of cells undergoing are terminally cell division. differentiated The acquisition B cells, which of genomic in physiologic aberrations conditions (cytogenetics are incapableprimary events,of underg left panel)oing maycell underpin division. the The transformation acquisition from of polyclonalgenomic toaberrations monoclonal (cytogeneticsplasma cells (stageprimary of monoclonalevents, left gammopathypanel) may ofunde undeterminedrpin the transformation significance, MGUS). from polyclonalAdditional to molecular monoclonal events plasma underlie cells the progression(stage of tomonoclonal smoldering multiplegammopathy myeloma of undetermined(SMM), multiple significance, myeloma (MM) MGUS). with clinicalAdditional disease molecular manifestations, events and underlie at the extreme the progressionpole, plasma to cellsmoldering leukemia multiple when >2 myeloma× 109 plasma (SMM), cells/L multiple are present myeloma in the (MM) peripheral with clbloodinical (ordisease >20% manifestations, of nucleated blood and at cells the are extreme constituted pole, byplasma plasma cell cells) leukemia [18]. when >2 × 109 plasmaIn fact, cells/L terminally are present differentiated in the peripheral plasma blood cells do (or not >20% undergo of nucleated cell division, blood cells however, are constitutedepigenetic by deregulation plasma cells) of gene [18]. expression has been proposed as a root cause of malignant transformationIn fact, terminally in MM differentiated [19]. Genome-wide plasma association cells do not studies undergo (GWAS) cell bydivision, Broderick however, and his epigeneticteam identified deregulation germline of variantsgene expression at 3p22.1, has 7p15.3, been andproposed 2p23.3 as as a risk root factors cause forof malignant developing transformationMGUS [15,20]. in TheirMM [19] associated. Genome gene-wide pairs association (DNMT3A studiesand (GWAS)DTNB, ULK4by Broderick and TRAK1, and hisDNAH11 team identified and CDCA7L, germlinerespectively) variants wereat 3p22.1, found 7p15.3, to be implicated and 2p23.3 in theas risk dysregulation factors for of the transcription factor encoding the MYC proto-oncogene [21]. Beksac et al. investigated the association of different human leukocyte antigen (HLA) polymorphisms with the risk of developing MM [22]. While the authors confirmed DRB5*01, C*07:02 g and B*07:02 g as potential risk-alleles for MM, they also illustrated their high correlation by linkage disequilibrium in Whites. Moreover, the cross-population analysis suggested that C*07 represents the only
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