PACSIN2 polymorphism is associated with thiopurine-induced hematological toxicity in children with acute lymphoblastic leukaemia undergoing maintenance therapy

Abstract

Adequate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), with 6-mercaptopurine as an essential component, is necessary for retaining durable remission. Interruptions or discontinuations of the therapy due to drug-related toxicities, which can be life threatening, may result in an increased risk of relapse. In this retrospective study including 305 paediatric ALL patients undergoing maintenance therapy, we systematically investigated the individual and combined effects of genetic variants of folate pathway enzymes, as well as of polymorphisms in PACSIN2 and ITPA, on drug-induced toxicities by applying a multi-analytical approach including logistic regression (LR), classification and regression tree (CART) and generalized multifactor dimensionality reduction (GMDR). In addition to the TPMT genotype, confirmed to be a major determinant of drug related toxicities, we identified the PACSIN2 rs2413739TT genotype as being a significant risk factor for 6-MP-induced toxicity in wild-type TPMT patients. A gene-gene interaction between MTRR (rs1801394) and MTHFR (rs1801133) was detected by GMDR and proved to have an independent effect on the risk of stomatitis, as shown by LR analysis. To our knowledge, this is the first study showing PACSIN2 genotype association with hematological toxicity in ALL patients undergoing maintenance therapy.

PACSIN2 rs2413739 influence on thiopurine pharmacokinetics: validation studies in pediatric patients

“…For ALL patients, an increased incidence of grade III/IV stomatitis and diarrhea during consolidation therapy in patients with variant T alleles could be confirmed, as previously reported [14]. Moreover, a trend for an association between PACSIN2 variants and severe HEM toxicities during maintenance therapy was found, confirming previously described data [34]. The results showed in this study are encouraging toward a significant effect of PAC-SIN2 variant on chemotherapy-induced adverse events occurrence although they are limited by the small number of individuals with already available clinical data.…”

“…It is therefore likely that the genetic effect of PACSIN2 rs2413739 on TPMT activity in ALL children emerges only under more physiological conditions, such as those found during the maintenance phase characterized by low-doses MTX and quite normal production and life cycle of RBC. A recent study has associated the PACSIN2 rs2413739 genotypes with the incidence of HEM toxicities during maintenance, this finding further supports the effect of this polymorphism in thiopurine biotransformation during this phase [34]. It is possible that the putative weak genetic influence of PACSIN2 varies with patient age and becomes more evident in younger patients because of higher measurable TPMT activity [35].…”

Thiopurine methyltransferase activity in children with acute myeloid leukemia

“…It has been demonstrated in vitro that individuals with the PACSIN2 rs2413739 CC genotype exhibited higher TPMT activities compared with carriers of other PACSIN2 variants (29). It was also confirmed that PACSIN2 rs2413739 CC-positive patients with ALL exhibited a lower incidence of gastrointestinal and hematological mercaptopurine toxicities in contrast to the ones with 25 CT and TT allele (29,30).…”

“…The same proportion of individuals with ultra-high TPMT activity was determined in a cohort of healthy Caucasian people (25)(26)(27)(28). Several candidate factors, including variable number tandem repeats (VNTRs) identified on the TPMT gene promotor, protein kinase C, casein kinase substrate in neurons 2 (PACSIN2) and SAM, responsible for the upregulation of TPMT activity were identified by the previous studies (25,26,29,30).…”

Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism

“…When this PhD project started, a few studies concerning varying enzyme activity or the connection between varying genotypes and adverse reactions in other thiopurine metabolizing enzymes had been published. Throughout these years, the complexity of thiopurine metabolism has been more extensive with reports of several polymorphisms within the metabolism of thiopurines (ITPA [166,167], HGPRT [142,168], IMPDH [168][169][170], XO [60,171], GST [172][173][174], GMPS [168], Rac1 [175], NT5C2 [176,177], PACSIN2 [178], genes in the mismatch repair system (MMR) [179], folate cycle [152][153][154] and transporters [56,175,[180][181][182]) and recently, pharmacogenetic testing of NUDT15, whose variants are more common in Asian populations, has been implemented in the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC) for thiopurine treatment [19,183] . Otherwise, so far, no other polymorphism has had the same extensive effect on thiopurine treatment as the genetic variants of TPMT.…”