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Page 250 Abaji et al. Cancer Drug Resist 2019;2:242-55 I http://dx.doi.org/10.20517/cdr.2018.24

from the NFATC2 gene, and for which it acts as an expression quantitative trait loci (eQTL) in pancreatic
tissue, had the strongest association signal with an increased risk of pancreatitis for carriers of the minor
allele. However, the validation analysis in a cohort of 33 cases and 285 controls who followed one of the
DFCI treatment protocols did not replicate this association. An association with pancreatitis was also
detected for minor alleles of rs13228878 and rs10273639 which reside on the same haplotype and are in
high linkage disequilibrium within the PRSS1-PRSS2 locus encoding for cationic and anionic trypsinogen,
respectively. The association was further confirmed in a replication analysis performed on samples from
patients of the Children’s Oncology Group (76 cases and 2,653 controls). Of note, these variants were
associated with an increase in the expression of PRSS1 gene and they have been previously linked to alcohol-
associated and sporadic pancreatitis in adults. Another interesting outcome of this study is the further
validation of the association between pancreatitis risk and SNPs within genes known to regulate trypsin
activation. Accordingly, minor alleles of rs17107315 in pancreatic secretory trypsin inhibitor (SPINK1),
rs10436957 in chymotrypsin C (CTRC), and rs4409525 in Claudin-2 (CLDN2) all had significant associations
with modulating the risk of ASNase-induced acute pancreatitis with directions and effects similar to
the previously reported findings. The authors also applied a targeted genotyping approach to test the
reproducibility of the association of the ULK2 variant rs281366 and RGS6 variant rs17179470 with the risk of
[15]
pancreatitis previously reported by the same group but the results were not significant .
Other less common toxicities
ASNase intolerance can also result in hepatotoxicity, abnormalities of hemostasis, hyperglycemia,
hyperlipidemia, and may also affect treatment outcome since it was shown that patients who experienced
a dose-limiting ASNase toxicity had a significantly worsened disease-free survival [2,8,10,12,18] . However, due
to the rarity of these toxicities, they were less frequently investigated. ASNase-induced hepatotoxicity
is one of the most common ASNase complications in adults treated for ALL but is rarely investigated
in genetic studies since most of such studies focus on the use of ASNase in pediatric patients. Given its
mechanism of action, ASNase induces amino acid stress response by depleting asparagine and glutamine.
This results in an excessive production of reactive oxygen species (ROS) and a subsequent increase in
mitochondrial permeabilization and eventual cell apoptosis; a process that has been linked to ASNase-
[6]
induced hepatotoxicity . In a candidate-gene analysis that involved 190 adult ALL patients enrolled on
CALGB-10102, the authors reported a significant association between homozygous carriers of the minor
allele of rs4880 in SOD2 gene, a mitochondrial enzyme that protects cells against ROS, and an increased risk
[6]
of hepatotoxicity following ASNase-based treatment .
Relapse
Relapse is a major cause of treatment failure in pediatric ALL as it was reported to arise in 11%-36% of patients
with high-risk B-precursor ALL [42-49] . The risk of relapse and treatment toxicity can be modulated by multiple
factors, and differences in genetic composition among patients have recently driven considerable attention [5,16] .
Several PGx studies reported that genomic variation was associated with higher risk of relapse in ALL
patients [42,50,51] . For example, in a GWAS that involved 2,535 children with newly diagnosed ALL that aimed at
targeting germline polymorphisms associated with relapse, the authors identified 5 SNPs linked to higher levels
[51]
of ASNase antibodies and 2 of those were associated with a higher relapse rate . In a more recent study that
investigated the contribution of germline genetic factors to relapse in 2,225 children treated according to the
Children’s Oncology Group trial AALL0232 protocol, the author reported that the group of relapse SNPs in the
more ASNase intensive treatment arm was overrepresented with SNPs linked to ASNase resistance or allergy .
[42]
Early reports have indicated that lower exposure to ASNase during ALL treatment can result in an
increased risk of relapse [52,53] , which lead a research team to hypothesising that genetic polymorphisms
of genes in asparagine pathway (i.e., ASNS, ATF5, and ASS1) can be associated with risk of event-free
survival and relapse leading to a study that involved 318 Caucasian children with ALL and an independent
[18]
replication cohort of 267 patients . Indeed, the authors identified a variant in the promotor of ATF5 gene,