A DNA repair pathway score predicts survival in human multiple myeloma: the potential for therapeutic strategy
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Alboukadel Kassambara1,2, Claire Gourzones-Dmitriev2, Surinder Sahota3, Thierry Rème1,2, Jérôme Moreaux1, Hartmut Goldschmidt4, Angelos Constantinou5, Philippe Pasero5, Dirk Hose4, Bernard Klein1,2,6
1 CHU Montpellier, Institute of Research in Biotherapy, Montpellier, F-34295 FRANCE;
2 INSERM, U1040, Montpellier, F-34197 France;
3 Cancer Sciences Unit, Faculty of Medicine, University of Southampton, UK
4 Medizinische Klinik V, Universitaetsklinikum Heidelberg, Heidelberg D-69120 GERMANY;
5 Institute of Human Genetics, CNRS-UPR1142, Montpellier F-34396 FRANCE;
6 Université MONTPELLIER1, UFR Médecine
Bernard Klein, email:
Keywords: DNA repair, Multiple Myeloma, prognosis
Received: December 24, 2013 Accepted: February 23, 2014 Published: February 24, 2014
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.
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