A DNA repair pathway score predicts survival in human multiple myeloma: the potential for therapeutic strategy

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.

Multiple Myeloma DREAM Challenge reveals epigenetic regulator PHF19 as marker of aggressive disease

“…ISS was the most important model feature in GIS's top-performing model as measured by the mean decrease in Gini coefficient (see Methods). A DNA repair signature previously associated with poor prognosis [16] was the second most important feature, while age ranked third (Supplemental Fig. 1).…”

Drug Targeting of Genomic Instability in Multiple Myeloma

“…The authors claim this DNA Repair (DR) score has the potential to identify patients whose tumor cells are dependent on specific DNA repair pathways. Recognition of such patients, might inform the design of treatments able to induce synthetic lethality through addiction to dysregulated DNA repair (Kassambara et al, 2015). Drugs with such potential include DNA-PKs inhibitors (NHEJ), RAD51 (HR), PARP1/2 (HR, alt NHEJ, BER), CHK2 (HR, alt NHEJ), and CHK1 (HR, NER) (Shaheen et al, 2011).…”

A Small-Molecule Inhibitor of RAD51 Reduces Homologous Recombination and Sensitizes Multiple Myeloma Cells to Doxorubicin

“…A growing body of evidence suggests that high expression of RAD51 correlates with an enhanced propensity of tumor cells for invasiveness ( 10 ), aggressiveness ( 11 ), poor prognosis ( 12 – 17 ), and resistance to DNA damage induced by chemotherapeutic drugs ( 17 – 21 ) or radiotherapy ( 22 ). Recently, high RAD51 expression was reported to have a negative prognostic value for both event-free and overall survival of MM patients ( 23 ). Targeting RAD51 has thus been proposed as a potential anti-cancer treatment, and downregulation of RAD51 by siRNA has been shown to selectively increase the chemotherapeutic sensitivity of human cancer cells relative to normal cells ( 24 ).…”