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

Abstract

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 × 10−3), 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 × 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.

ATF5 polymorphisms influence ATF function and response to treatment in children with childhood acute lymphoblastic leukemia

“…13 Recent genome-wide analysis identified genes of aspartate metabolism as contributors to asparaginase sensitivity in vitro. 38 Among the top-ranking genes identified in that study, an association of ASS1 polymorphisms with in vitro asparaginase sensitivity in ALL patient samples and HapMap cell lines was found. 38 Given their intronic positions, these polymorphisms were not tested in our study.…”

“…38 Among the top-ranking genes identified in that study, an association of ASS1 polymorphisms with in vitro asparaginase sensitivity in ALL patient samples and HapMap cell lines was found. 38 Given their intronic positions, these polymorphisms were not tested in our study. Among those that we analyzed, 2 SNPs, G34T and G1343T, which were associated with lower EFS in the test cohort, did not sustain correction for multiple testing and were not further analyzed in the replication cohort.…”

Association of Aminoacyl-tRNA Synthetases with Cancer

“…LRS, MRS, arginyl-tRNA synthetase (RRS), aspartyl-tRNA synthetase (DRS), mitochondrial DRS, and mitochondrial asparaginyl-tRNA synthetase (NRS) can deregulate cellular energetics [8][9][10][11]. Secreted ARSN, glycyl-tRNA synthetase (GRS), lysyl-tRNA synthetase (KRS), threonyl-tRNA synthetase (TRS), tryptophanyl-tRNA synthetase (WRS), tyrosyltRNA synthetase (YRS), and AIMP1 can impact tumor-promoting inflammation, angiogenesis, and metastasis [12][13][14][15].…”

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

“…To date, only 10 pharmacogenetics studies analyzing L-ASP have been performed in pediatric ALL [34,[41][42][43][44][45][46][47][48][49]. Among them, six specifically focused on the analysis of the risk to L-ASP hypersensitivity, finding the most remarkable results with 15 polymorphisms located at GRIA1, HLA-DRB1, NFATC2 and ASNS (Table 1) [34,[41][42][43][44]49].…”