Abstract
DNA repair is critical to resolve extrinsic or intrinsic DNA damage to ensure regulated gene transcription and DNA replication. These pathways control repair of double strand breaks, interstrand crosslinks, and nucleotide lesions occurring on single strands. Distinct DNA repair pathways are highly inter-linked for the fast and optimal DNA repair. A deregulation of DNA repair pathways may maintain and promote genetic instability and drug resistance to genotoxic agents in tumor cells by specific mechanisms that tolerate or rapidly bypass lesions to drive proliferation and abrogate cell death. Multiple Myeloma (MM) is a plasma cell disorder characterized by genetic instability and poor outcome for some patients, in which the compendium of DNA repair pathways has as yet not been assessed for a disease-specific prognostic relevance. We design a DNA repair risk score based on the expression of genes coding for proteins involved in DNA repair in MM cells. From a consensus list of 84 DNA repair genes, 17 had a bad prognostic value and 5 a good prognostic value for both event-free and overall survival of previously-untreated MM patients. The prognostic information provided by these 22 prognostic genes was summed within a global DNA repair score (DRScore) to take into account the tight linkage of repair pathways. DRscore was strongly predictive for both patients' event free and overall survivals. Also, DRscore has the potential to identify MM patients whose tumor cells are dependent on specific DNA repair pathways to design treatments that induce synthetic lethality by exploiting addiction to deregulated DNA repair pathways.
Highlights
Multiple myeloma (MM) is a plasma cell disease arising from the malignant transformation of postfollicular B cells and affects 22000 new individuals in the EU or US each year[1]
This disease is characterized by extensive molecular heterogeneity in multiple myeloma cells (MMCs) and diversity in overall survival of patients, which ranges from several months to more than ten years[2,3,4]
Base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR) operate on nucleotide lesions occurring on single strands
Summary
Multiple myeloma (MM) is a plasma cell disease arising from the malignant transformation of postfollicular B cells and affects 22000 new individuals in the EU or US each year[1]. Additional molecular defects target various genes, which deregulate the p53 pathway (monoallelic deletion of the TP53 www.impactjournals.com/oncotarget gene and TP53 mutations), NK-B pathway (mutations or amplifications), RAS pathway (mutations), or MYC pathway (amplification, rare translocations)[7, 8] These abnormalities may concur to deregulate cell cycle checkpoints and impact on the array of DNA repair pathways[9]. Since the MM clone evolves at the genome level as disease progresses, it is highly likely that deregulated DNA repair pathways are implicated in clonal evolution[9, 17, 18] These pathways are of relevance for genotoxic drugs used to treat patients with MM, presently doxorubicin, melphalan, cyclophosphamide, and bendamustine[9]. The data reveals specific patterns of gene expression in MMCs that have prognostic value for both event free and overall survival of newly-diagnosed patients
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