Polymorphism of ITPA 94C&gt;A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine

Rosalina, Wan; Teh, Lay Kek; Mohamad, Norsarwany; Nasir, Ariffin; Yusoff, Rozita; Baba, Aziz; Salleh, Mohd Zaki

doi:10.1111/j.1365-2710.2011.01272.x

Cited by 40 publications

(36 citation statements)

References 15 publications

(33 reference statements)

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“…In a study of 62 IBD patients, positive association was observed between ITPA C94A and increased adverse events other than leucopenia [35]. In ALL patients, this variant was associated with the pyrexia and hepatotoxicity [36] and severe febrile neutropenia, indicating the clinical relevance of this variant in 6-MP dose adjustment [37]. In the current study, we also investigated the association of ITPA 94 C→ A with myelotoxicity, which is consistent with Marinaki et al who showed association with leucopenia and a high frequency of febrile episodes [35].…”

Section: Discussionmentioning

confidence: 97%

Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia

Dorababu

Nagesh

Linga

et al. 2011

Eur J Clin Pharmacol

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Section: Discussionmentioning

confidence: 97%

Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia

Dorababu

Nagesh

Linga

et al. 2011

Eur J Clin Pharmacol

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“…On the other hand, Guatemalan admixed populations have one of the highest observed toxicity risk rates for treatments based on thiopurine drugs (17 %, see Table 1). This percentage could be an underestimate, considering that at least 20 additional mutant variants have been identified in TPMT (TPMT*3D, *4, *5, *6, *7, *8, *10, *23, *28, etc) and that SNPs in other genes, such as inosine triphosphate pyrophosphohydrolase (ITPA 94C>A) also affect thiopurine metabolism (3, 15, 29, 50). …”

Section: Discussionmentioning

confidence: 99%

Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia

Garrido¹,

Santizo²,

Müllers³

et al. 2013

Med Oncol

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Thiopurine S-methyltransferase (TPMT) polymorphisms affect the enzyme's activity and are predictive for the efficacy and toxicity of thiopurine treatment of acute lymphoblastic leukemia (ALL), autoimmune diseases and organ transplants. Because inter-ethnic differences in the distribution of these polymorphisms have been documented, we sequenced the TMPT gene in 95 Guatemalans, yet identified no new alleles. We also determined the frequency of the TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C alleles in 270 admixed and 177 indigenous pediatric patients with ALL and healthy subjects from Guatemala using TaqMan assays and DNA sequencing. Among the 447 subjects genotyped, 10.0% of the ALL cases and 13.6% of the healthy controls were heterozygous for one of the four TPMT variants screened. The genotype frequencies in ALL and control populations were 0.7% and 1.7% for TPMT*1/*2, 7.4% and 10% for TPMT*1/*3A, 0.3% and 0% for TPMT*1/*B, and 1.5% and 1.1% for TPMT*1/*C, respectively (p= 0.30). No statistically significant differences between admixed and indigenous ALL (p= 0.67) or controls (p= 0.41) groups were detected; however 17% of the admixed healthy group bore one TPMT mutant allele and they have one of the highest reported frequencies of TPMT mutant allele carriers. Because of the clinical implications of these variants for therapeutic response, TPMT allele testing should be considered in all Guatemalan patients to reduce adverse side-effects from thiopurine drug treatments.

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“…The ITPA variant allele (rs1127354) is associated with nonfunctionality of the enzyme and is found with an allelic frequency ranging from 5 to 19%, with the lower end of the range seen in Caucasian populations and the higher range seen in Asian populations [96]. The polymorphism is associated with higher concentrations of methylated nucleotide metabolites of 6-MP in cells, as well as higher incidence of severe hepatotoxicity, even after adjustment for TPMT genotype [62][63][64][65][66]. Furthermore, a variant in the PACSIN2 gene has been found to modulate the activity of TPMT and is also independently associated with severe gastrointestinal toxicity due to 6-MP [70].…”

Section: Gastrointestinal Toxicitymentioning

confidence: 97%

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

Maxwell

Cole

2017

Curr Hematol Malig Rep

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Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

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Polymorphism of ITPA 94C>A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine

Abstract: Our results suggest that ITPA 94C>A testing, but not TPMT testing, may help in minimizing the adverse effects of 6-MP in Malaysian patients. However, whether this is true in clinical practice requires a larger study and formal randomized controlled evaluation.

Cited by 40 publications

References 15 publications

Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia

Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia

Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

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