Page 93 - Read Online

Page 260 Franca et al. Cancer Drug Resist 2019;2:256-70 I http://dx.doi.org/10.20517/cdr.2019.004

Table 1. Putative pharmacogenetic indicator for thiopurines
Influence on mercaptopurine
Gene Protein function Genetic variants Ref.
response in patients
TPMT S-methylation* rs1800462 Severe leukopenia and [36]
(*2, 238C>G, pAla80Pro) hematological toxicity in
carriers of the variant alleles
rs1800460
(*3B, 460G>A, p.Ala154Thr)
rs1142345
(*3C, 719A>G, p.Tyr240Cys)
NUDT15 Diphosphatase, catalyses rs116855232 Thiopurine intolerance [41]
the hydrolysis of nucleoside (415C>T, p.Arg139Cys) and adverse drug reaction
triphosphates and their oxidized in carriers of the loss-of- [42]
forms rs147390019 function NUDT15 genetic
(416G>A, p.Arg139His) polymorphisms [43]
rs186364861 [36]
(52G>A, p.Val18Ile)

rs746071566
(Insertion 36_37insGGAGTC p.Val18_
Val19insGlyVal)
PACSIN2 Vesicle formation, endocytosis rs2413739 (T>C) Severe gastrointestinal and [70]
and caveole biogenesis haematological toxicities in TT
genotype patients [71]
ITPA Pyrophosphatase that hydrolyzes rs1127354 (94C>A, p.Pro32Thr) Severe febrile neutropenia and [59]
the non-canonical purine hepatotoxicity in carriers of
nucleotides inosine triphosphate rs7270101 (IV2 +21A>C) the variant alleles [6]

*A natural substrate for this enzyme has yet to be identified. ITPA: Inosine triphosphate pyrophosphatase; NUDT15: nucleotide
triphosphate diphosphatase; PACSIN2: Protein kinase C and casein kinase substrate in neurons protein 2 TPMT: Thiopurine
S-methyltransferase

[20]
co-factor molybdopterin has been postulated but not fully demonstrated yet . TPMT is encoded by a 27
[21]
kb gene, composed of 10 exons, located in the short arm of chromosome 6 . Its expression varies and the
patient genetic background is responsible for the observed interindividual differences in clinical efficacy
[22]
and hematologic toxicity of thiopurine therapy . Recent genome-wide association studies (GWAS) have
provided evidences of TPMT as the only monogenic trait that influences the TPMT phenotype, finding that
only variants in TPMT gene are significantly associated with TPMT activity in ALL children at genome-
-61
wide level (n = 1,026; P = 8.6 × 10 ) and in a mixed-population (two cohorts of adult healthy volunteers
-72 [23,24]
and one of pediatric ALL patients, n = 1,212; P = 1.2 × 10 ) . TPMT activity is inherited as an autosomal
codominant trait and approximately 1 in 300 individuals has very low TPMT activity, 10% have intermediate
[25]
activity and 89% show normal/high activity . Indeed 10% of Europeans are positive for a genetic variant in
[26]
TPMT and 0.5% are TPMT completely defective . Studies that correlate TPMT genotype and phenotype in
different populations show that there are more than 38 allelic variants responsible for a possible impairment
[27]
of the enzyme activity . However, only few alleles, such as TPMT*2 and TPMT*3, comprise 95% of the loss
of function variants and therefore are clinically relevant. TPMT*2 allele (Single Nucleotide Polymorphism
(SNP) rs1800462) is defined by the 238G>C transversion and the p.Ala80Pro amino acid substitution,
whereas the TPMT*3 family alleles are defined by the SNPs 460G>A (rs1800460, p.Ala154Thr) and 719A>G
(rs1142345, p.Tyr240Cys). In particular, TPMT*3A is the haplotype characterized by both 460G>A and
719A>G transitions, TPMT*3B corresponds to the SNP rs1800460 alone and TPMT*3C to the single SNP
[27]
rs1142345 . Genetic variants affecting TPMT activity are different among the main ethnic groups: indeed,
the TPMT*3A is the variant most present in Europeans, while TPMT*3C is the most frequent in African
[28]
and South-east Asian populations (allele frequency of 3%) . In Africans, an additional allele putatively
[29]
presenting reduced enzymatic activity, TPMT*8, identified by the polymorphism rs56161402, is present .
All these genetic variations lead to TPMT activity alterations: several studies have shown that the mechanism
for decreased levels of TPMT protein and catalytic activity is the enhanced degradation of TPMT allozymes