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Abaji et al. Cancer Drug Resist 2019;2:242-55 I http://dx.doi.org/10.20517/cdr.2018.24 Page 249

In a work that tackled the PGx of ASNase through candidate-gene approach, by the association between
SNPs in ASNS, ATF5 and ASS1 genes and ASNase induced allergy and pancreatitis was investigated in a
discovery cohort of 285 ALL patients and a replication cohort of 248 patients who were treated according
to Dana-Farber Cancer Institute ALL Consortium protocols. The authors reported a significant association
between a 14-bp tandem-repeat polymorphism rs3832526 in ASNS gene and both of these toxicities as
patients homozygous for the triple repeat allele (3R) had the complications more frequently than other
genotype groups. Moreover, when analysing the effect of possible haplotypes, they found that the ASNS
haplotype *1 harbouring double repeat (2R) allele conferred a protective effect from these toxicities and
its association with allergy was further validated in an independent replication cohort. Furthermore, they
showed that one of the subtypes of this haplotype was associated with reduced in vitro sensitivity to ASNase
[10]
in lymphoblastoid cell lines .

It is worth mentioning that in a study including 472 Japanese children with ALL who were treated on a
protocol that included E. coli derived asparaginase, the authors followed a candidate-gene approach aimed
at replicating the associations found with GRIA1 rs4958351, NFATC2 rs6021191, and ANSN rs3832526. The
authors reported no significant association between any of the variants and HSRs which suggests that the role
[40]
of these variants might be influenced by ethnic specific differences in genetic structure surrounding them .
Another work followed an exome-wide association study approach which was performed on 302 children
with ALL treated according to DFCI protocols and the results were validated in an independent group of
282 patients following protocols of the same institution. The authors interrogated around 4.5 thousand SNPS
distributed across 3,802 genes and reported 12 associations with ASNase complications in the discovery
cohort including 3 with allergy, 3 with pancreatitis and 6 with thrombosis along, with a strong additive effect
of combining more than one polymorphism. Interestingly, rs3809849 in the MYBBP1A gene was associated
with allergy, pancreatitis, thrombosis, event-free survival (EFS) and overall survival, while rs11556218 in IL16
gene and rs34708521 in SPEF2 gene were both associated with thrombosis and pancreatitis. Importantly, the
[41]
association of each of these three polymorphisms with pancreatitis was replicated in the validation cohort .
Of note, our search results could not identify other original research work that investigated the PGx of
ASNase-induced thrombosis, which could be an interesting field for future studies.

In a GWAS study of ASNase-induced pancreatitis that involved ALL patients treated following St Jude
Children’s Research Hospital and the Children’s Oncology Group protocols, the discovery group was
composed of 5,185 children and young adults with ALL and was replicated in an independent case-control
group of 213 patients. While the authors reported no significant association of common variants at the
GWAS level, they detected a significant association for a rare nonsense variant rs199695765 in CPA2 gene.
Interestingly, in a subsequent gene-level investigation, 16 SNPs in this gene were significantly associated with
[35]
pancreatitis with around 54% of carriers of at least one of these polymorphisms ended up developing it .

In another GWAS study of 700 children who were treated following the NOPHO ALL2008 protocol, the
authors interrogated around 1.5 million SNPs and found 27 significant associations with ASNase related
pancreatitis. rs281366 variant in ULK2 gene showed the strongest association with pancreatitis, and
interestingly, 14 of the 27 associations were of polymorphisms in this same gene. In a sub-analysis focusing
on patients who were less than 10 years old, rs17179470 in RGS6 was strongly associated with pancreatitis.
Moreover, in this particular subgroup, more than half of the cases carried one of these two risk alleles and
the risk of pancreatitis associated with carrying both alleles was additive. Of noteworthy, ULK2 gene is
[15]
involved in autophagy, and RGS6 regulates G-protein signaling regulating cell dynamics .

In a larger and more recent multi-centric study lead by researchers from the same group, the authors
investigated the risk of ASNase-associated pancreatitis in a discovery cohort of 244 cases and 1320 controls
[15]
through GWAS analysis . rs62228256, a variant located in a noncoding region of the genome upstream