Genome Instability in Multiple Myeloma: Facts and Factors

Abstract

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

Optimization of Plasma Cell Enrichment for CNV Detection by SNP Array and Mlpa

“…From a genetic point of view, MM is a complex disease, with a high level of heterogeneity of which mechanisms of occurrence and evolution are not fully understood (Aksenova, Zhuk et al 2021). This heterogeneity in same cases of MM is translated in the presence of clone and subclone.…”

Tracking Clonal Evolution of Multiple Myeloma Using Targeted Next-Generation DNA Sequencing

“…Anti-myeloma therapy acts as a selection force for genetically distinct MM cells. Mutation gain observed during MM progression may therefore have occurred by selection and expansion of pre-existing very rare variants which could not be identified at the achieved sequencing depth in the initial sample (or were localized in non-sequenced tumor sites) or by the emergence of new variants due to the use of genotoxic drugs (e.g., melphalan, cyclophosphamide, bendamustine and doxorubicin), especially in the context of impaired DNA repair mechanisms [ 44 ].…”

Multiple Myeloma: Bioinformatic Analysis for Identification of Key Genes and Pathways

“…A set of 114 DEGs in myeloma plasma cells involved in the progression of the disease were collected from different scientific publications 11 - 47 and databases ( https://www.ncbi.nlm.nih.gov/ ). The following search terms were used: multiple myeloma, gene expression, heterogeneity, mutational profiles, and genetic predisposition.…”