Abstract
Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50% of growth (inhibitory concentration (IC)50). In CEU lines, we tested 2 390 203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P<0.001) and gene level (P<0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC50. The aspartate metabolism pathway was the most overrepresented among 199 pathways evaluated (P=8.1 × 10−3), with primary involvement of adenylosuccinate lyase and aspartyl-tRNA synthetase genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (P=5.5 × 10−5). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity.
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Acknowledgements
We thank the patients and their families, and our research faculty and staff for participating. We also thank Nancy Kornegay and Mark Wilkinson for database and computer expertise, and Yaqin Chu, May Chung, Natalya Lenchik, Margaret Needham, Emily Melton and Siamac Salehy for outstanding technical assistance. This work was supported by NCI CA78224, CA36401 and the NIH/NIGMS Pharmacogenomics Research Network (U01GM92666) and by ALSAC.
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Chen, SH., Yang, W., Fan, Y. et al. A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity. Leukemia 25, 66–74 (2011). https://doi.org/10.1038/leu.2010.256
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DOI: https://doi.org/10.1038/leu.2010.256
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