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

Awada, Hassan; Thapa, Bicky; Awada, Hussein; Dong, Jingjing; Gurnari, Carmelo; Hari, Parameswaran; Dhakal, Binod

doi:10.3390/cells10081961

Cited by 20 publications

(12 citation statements)

References 105 publications

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“…GEP-based marker SKY92 is a standardized tool for risk stratification that provides additional information to the anamneses of patients with MM. SKY92 allows for risk stratification in relatively homogenous subgroups of patients and provides added value in combination with clinical markers and FISH, which by itself does not capture the genomic complexity of MM ( 27 , 34 ). SKY92 stratifies MM patients into high-risk or standard-risk group irrespective of treatment regime and relapse setting.…”

Section: Discussionmentioning

confidence: 99%

“…In parallel with defining staging systems on the basis of clinical variables, the role of cytogenetics in multiple myeloma was being investigated. Cytogenetics has shown to play a role in other hematologic malignancies but was difficult to study in MM mainly due to low proliferation of myeloma cells, which hampered karyotyping ( 27 ). The emergence of FISH enabled the analysis of genetic aberrations independent from cell cycle phases and thereby allowed research of the prognostic value of single chromosomal abnormalities ( 28 ).…”

Section: The Challenge Of Defining the High-risk Patientmentioning

confidence: 99%

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Gene Expression Profiling in Multiple Myeloma: Redefining the Paradigm of Risk-Adapted Treatment

et al. 2022

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Multiple myeloma is a blood cancer characterized by clonal proliferation of plasma cells in the bone marrow. In recent years, several new drugs have been added to the therapeutic landscape of multiple myeloma, which have contributed to increased survival rates. However, while the use of therapeutics has evolved, there is still a group of high-risk patients who do not benefit from current treatment strategies. Risk stratification and risk-adapted treatment are crucial to identify the group of patients with urgent need for novel therapies. Gene expression profiling has been introduced as a tool for risk stratification in multiple myeloma based on the genetic make-up of myeloma cells. In this review we discuss the challenge of defining the high-risk multiple myeloma patient. We focus on the standardized analysis of myeloma cancer cells by gene expression profiling and describe how gene expression profiling provides additional insights for optimal risk-adapted treatment of patients suffering from multiple myeloma.

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Section: Discussionmentioning

confidence: 99%

Section: The Challenge Of Defining the High-risk Patientmentioning

confidence: 99%

Gene Expression Profiling in Multiple Myeloma: Redefining the Paradigm of Risk-Adapted Treatment

et al. 2022

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“…Somatic mutations affecting MAPK/ERK (e.g., KRAS , BRAF , PTPN11 , RASA2 ), NF-KB (e.g., NFKB2 ), cell cycle (e.g., CCND1 ), DNA repair (e.g., TP53 ) and RNA metabolism (e.g., DIS3 , FAM46C ) signaling pathways were detected. Dysregulation of these pathways is an established mechanism in malignant PCs [ 5 , 41 , 54 , 55 , 56 , 65 , 66 , 67 , 68 , 69 ]. These SNVs have previously been shown to contribute to part of the genetic landscape of the myeloma precursor conditions MGUS and SMM as well [ 5 , 8 , 22 , 23 , 24 , 25 , 70 ].…”

Section: Discussionmentioning

confidence: 99%

The Dynamics of Nucleotide Variants in the Progression from Low–Intermediate Myeloma Precursor Conditions to Multiple Myeloma: Studying Serial Samples with a Targeted Sequencing Approach

Oben

Cosemans

Geerdens

et al. 2022

Cancers

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Multiple myeloma (MM), or Kahler’s disease, is an incurable plasma cell (PC) cancer in the bone marrow (BM). This malignancy is preceded by one or more asymptomatic precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). The molecular mechanisms and exact cause of this progression are still not completely understood. In this study, the mutational profile underlying the progression from low–intermediate risk myeloma precursor conditions to MM was studied in serial BM smears. A custom capture-based sequencing platform was developed, including 81 myeloma-related genes. The clonal evolution of single nucleotide variants and short insertions and deletions was studied in serial BM smears from 21 progressed precursor patients with a median time of progression of six years. From the 21 patients, four patients had no variation in one of the 81 studied genes. Interestingly, in 16 of the 17 other patients, at least one variant present in MM was also detected in its precursor BM, even years before progression. Here, the variants were present in the pre-stage at a median of 62 months before progression to MM. Studying these paired BM samples contributes to the knowledge of the evolutionary genetic landscape and provides additional insight into the mutational behavior of mutant clones over time throughout progression.

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“…Primary cytogenetic aberrations are thought to be an early event in the transformation from polyclonal to monoclonal plasma cells. The acquisition of trisomies of odd-numbered chromosomes (3, 5, 7, 9, 11, 15, 19 and 21) characterizes the hyperdiploid MM subtype, whereas translocations of the IGH locus at chromosome 14q32 with various partner chromosomes (most frequently 4, 6, 11, 16, and 20) characterizes the nonhyperdiploid subtype [123]. MM is characterized by extreme genetic heterogeneity both among patients, presenting their own composite of chromosomal rearrangements and gene mutations, and intraclonally, with most of the patients presenting a complex subclonal structure [46].…”

Section: Multiple Myelomamentioning

confidence: 99%

KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders

Vendramini

Bomben

Pozzo

et al. 2022

Cancers

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KRAS mutations account for the most frequent mutations in human cancers, and are generally correlated with disease aggressiveness, poor prognosis, and poor response to therapies. KRAS is required for adult hematopoiesis and plays a key role in B cell development and mature B cell proliferation and survival, proved to be critical for B cell receptor-induced ERK pathway activation. In mature B cell neoplasms, commonly seen in adults, KRAS and RAS-MAPK pathway aberrations occur in a relevant fraction of patients, reaching high recurrence in some specific subtypes like multiple myeloma and hairy cell leukemia. As inhibitors targeting the RAS-MAPK pathway are being developed and improved, it is of outmost importance to precisely identify all subgroups of patients that could potentially benefit from their use. Herein, we review the role of KRAS and RAS-MAPK signaling in malignant hematopoiesis, focusing on mature B cell lymphoproliferative disorders. We discuss KRAS and RAS-MAPK pathway aberrations describing type, incidence, mutual exclusion with other genetic abnormalities, and association with prognosis. We review the current therapeutic strategies applied in mature B cell neoplasms to counteract RAS-MAPK signaling in pre-clinical and clinical studies, including most promising combination therapies. We finally present an overview of genetically engineered mouse models bearing KRAS and RAS-MAPK pathway aberrations in the hematopoietic compartment, which are valuable tools in the understanding of cancer biology and etiology.

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

Cited by 20 publications

References 105 publications

Gene Expression Profiling in Multiple Myeloma: Redefining the Paradigm of Risk-Adapted Treatment

Gene Expression Profiling in Multiple Myeloma: Redefining the Paradigm of Risk-Adapted Treatment

The Dynamics of Nucleotide Variants in the Progression from Low–Intermediate Myeloma Precursor Conditions to Multiple Myeloma: Studying Serial Samples with a Targeted Sequencing Approach

KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders

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