Abstract
BackgroundNucleotide Excision Repair (NER) is a major pathway of mammalian DNA repair that is associated with drug resistance and has not been well characterized in acute lymphoblastic leukemia (ALL). The objective of this study was to explore the role of NER in relapsed ALL patients. We hypothesized that increased expression of NER genes was associated with drug resistance and relapse in ALL.MethodsWe performed secondary data analysis on two sets of pediatric ALL patients that all ultimately relapsed, and who had matched diagnosis-relapse gene expression microarray data (GSE28460 and GSE18497). GSE28460 included 49 precursor-B-ALL patients, and GSE18497 included 27 precursor-B-ALL and 14 T-ALL patients. Microarray data were processed using the Plier 16 algorithm and the 20 canonical NER genes were extracted. Comparisons were made between time of diagnosis and relapse, and between early and late relapsing subgroups. The Chi-square test was used to evaluate whether NER gene expression was altered at the level of the entire pathway and individual gene expression was compared using t-tests.ResultsWe found that gene expression of the NER pathway was significantly increased upon relapse in patients that took 3 years or greater to relapse (late relapsers, P = .007), whereas no such change was evident in patients that relapsed in less than 3 years (early relapsers, P = .180). Moreover, at diagnosis, the NER gene expression of the early relapsing subpopulation was already significantly elevated over that of the late relapsing group (P < .001). This pattern was validated by an ‘NER score’ established by averaging the relative expression of the 20 canonical NER genes. The NER score at diagnosis was found to be significantly associated with disease-free survival in precursor-B-ALL (P < .001).ConclusionPatients are over two times more likely to undergo early relapse if they have a high NER score at diagnosis, hazard ratio 2.008, 95% CI (1.256–3.211). The NER score may provide a underlying mechanism for “time to remission”, a known prognostic factor in ALL, and a rationale for differential treatment.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, treatment has improved dramatically due to the ability to stratify patients into groupsThe basis of genotoxic chemotherapy is to induce DNA damage in rapidly growing cells to critically damage and eradicate the cancer [9]
We compared paired samples from 27 patients with precursor-B-acute lymphoblastic leukemia (ALL); we found that 15/20 Nucleotide Excision Repair (NER) genes had higher expression at the time of relapse than at the time of diagnosis (Fig. 1a)
In the Hogan dataset (49 patients, precursor-B-ALL), we found that 10/20 NER genes were overexpressed at time of relapse compared to time of diagnosis (Fig. 1b), indicating that there was no significant change in the overall expression of the pathway (P = 1.0), three genes were individually significantly upregulated
Summary
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, treatment has improved dramatically due to the ability to stratify patients into groupsThe basis of genotoxic chemotherapy is to induce DNA damage in rapidly growing cells to critically damage and eradicate the cancer [9]. NER is a versatile DNA repair pathway and is involved in remediating damage induced by anthracyclines, cyclophosphamide and other agents [20, 21]. This pathway requires 20 canonical proteins to complete repair [22]. There is little to no information on the role of NER in childhood ALL resistance or relapse. Nucleotide Excision Repair (NER) is a major pathway of mammalian DNA repair that is associated with drug resistance and has not been well characterized in acute lymphoblastic leukemia (ALL). The objective of this study was to explore the role of NER in relapsed ALL patients.
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