title: Genomic instability in multiple myeloma: mechanisms and therapeutic implications.
abstract: BACKGROUND
  Clonal plasma cells in multiple myeloma (MM) are typified by their nearly universal aneuploidy and the presence of recurrent chromosomal aberrations reflecting their chromosomal instability. Multiple myeloma is also recognized to be heterogeneous with distinct molecular subgroups. Deep genome sequencing studies have recently revealed an even wider heterogeneity and genomic instability with the identification of a complex mutational landscape and a branching pattern of clonal evolution.
  
  
  METHODS
  Despite the lack of full understanding of the exact mechanisms driving the genomic instability in MM, recent observations have correlated these abnormalities with impairments in the DNA damage repair machinery as well as epigenetic changes. These mechanisms and the resulting therapeutic implications will be the subject of this review.
  
  
  CONCLUSIONS
  By providing growth advantage of the fittest clone and promoting the acquisition of drug resistance, genomic instability is unarguably beneficial to MM cells, however, it may also well be its Achilles heal by creating exploitable vulnerabilities. As such, targeting presumptive DNA repair defects and other oncogenic addictions represent a promising area of clinical investigation. In particular, by inducing gene or pathway dependencies not present in normal cells, genomic instability can generate targets of contextual synthetic lethality in MM cells.
authors.affiliation: University of Calgary, Division of Hematology and Bone Marrow Transplant, Hospital Drive NW, Calgary, AB T2N4N1, Canada.
authors.forename: Paola
authors.initials: P
authors.lastname: Neri
authors.forename: Nizar J
authors.initials: NJ
authors.lastname: Bahlis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002869:Chromosome Aberrations / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents