A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity.

Asparaginase is an important component of treatment for 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 employed 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 (IC50). In CEU lines, we tested 2,390,203 SNP genotypes at the individual SNP (p < 0.001) and the 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 over-represented among 199 pathways evaluated (p = 8.1 7 10 123), with primary involvement of ADSL and DARS 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 7 10 125). 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