Abstract
Abstract
Double strand break repair and its relationship with genomic instability have been well studied in Acute Lymphocytic Leukemia (ALL). In contrast, base repair mechanisms, such as Nucleotide Excision Repair (NER) have not been well characterized in ALL. The NER pathway addresses base damage resulting in helix distortion and replication stalling, making it important for all types of cancer. Since increased NER is a known mechanism of chemotherapeutic drug resistance, we hypothesize that there will be an increase in the expression of the NER genes at the time of relapse in ALL patients. We have studied the role of NER in ALL by secondary analysis of 2 independent gene expression microarray studies performed by Staal et al. (Set A, GSE18497) and Hogan et al. (Set B, GSE28460). Both studies analyzed matched samples of ALL patients at diagnosis and relapse (41 and 49 pairs, respectively). In Set A we found that 17/20 NER genes have higher expression at the time of relapse, than at the time of diagnosis. 4 of these genes were individually significant. However, in a subset analysis of these data sets, based on the time to relapse, patients who have early (<3 years) vs. late (>3 years) relapse gave distinct results. In Set A, 18/20 NER genes were upregulated at the time of diagnosis in the early relapse group vs. the late relapse group. 4 genes were individually significantly increased. In set B, NER gene expression at the time of diagnosis of patients in the early relapse group was increased in all 20 NER genes when compared to the late relapse group. 7 genes showed individually significant increases in expression. In addition patients in the late relapse group showed an increase in expression of many of the NER genes at time of relapse when compared to time of diagnosis. In conclusion, there are two types of ALL. Early relapsing ALL manifests high NER gene expression at diagnosis with little change at relapse. Late relapsing ALL manifests low NER gene expression at diagnosis with substantial increase at the time of relapse. NER gene expression at the time of diagnosis may allow us to predict which patients are at greatest risk for earlier relapse. This will allow pharmacogenomic targeting of each type of ALL.
Citation Format: Omar Ibrahim, Homood As Sobeai, Stephen G. Grant, Jean J. Latimer. Nucleotide excision repair gene expression in childhood acute lymphocytic leukemia is a predictor of early relapse. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1552.