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

Abstract

The aim of the study was to validate the impact of the single-nucleotide polymorphism rs2413739 (T > C) in the PACSIN2 gene on thiopurines pharmacological parameters and clinical response in an Italian cohort of pediatric patients with acute lymphoblastic leukemia (ALL) and inflammatory bowel disease (IBD). In ALL, PACSIN2 rs2413739 T allele was associated with a significant reduction of TPMT activity in erythrocytes (p = 0.0094, linear mixed-effect model, multivariate analysis considering TPMT genotype) and increased severe gastrointestinal toxicity during consolidation therapy (p = 0.049). A similar trend was present also for severe hematological toxicity during maintenance. In IBD, no significant effect of rs2413739 could be found on TPMT activity, however azathioprine effectiveness was reduced in patients carrying the T allele (linear mixed effect, p = 0.0058). In PBMC from healthy donors, a positive correlation between PACSIN2 and TPMT protein concentration could be detected (linear mixed effect, p = 0.045). These results support the role of PACSIN2 polymorphism on TPMT activity and mercaptopurine adverse effects in patients with ALL. Further evidence on PBMC and pediatric patients with IBD supports an association between PACSIN2 variants, TPMT activity, and thiopurines effects, even if more studies are needed since some of these effects may be tissue specific.

Genome wide association studies for treatment‐related adverse effects of pediatric acute lymphoblastic leukemia

“…Furthermore, in an independent validation cohort of ALL patients enrolled in the AIEOP‐BFM 2000 protocol, the association between rs2413739 and GI toxicity was confirmed ( p = .032) (Stocco, Yang, et al, 2012). In another study, Franca and collaborators validated the effect of rs2413739 T variant on TPMT activity (that was significantly reduced in erythrocytes, p = .0094) and on GI toxicity (that was significantly increased, p = .049) in a cohort of 280 ALL patients enrolled on the AIEOP‐BFM ALL 2009 protocol during consolidation therapy (Franca, Stocco, et al, 2019; Franca, Zudeh, et al, 2019). While TPMT variants seem to be the strongest determinants of interindividual variability in TPMT activity, PACSIN2 could have a role in specific tissues and patient subgroups that however still need to be fully evaluated.…”

“…These immunomodulatory drugs are used also in inflammatory bowel disease (IBD) treatment. They have a low therapeutic index: excessive myelosuppression and treatment failure can be the consequence of pharmacokinetic inter individual variability also due to pharmacogenetic variants (Franca, Stocco, et al, 2019; Franca, Zudeh, et al, 2019). Thiopurines do not present an intrinsic activity: indeed, they undergo a multistep metabolic conversion that leads to the formation of active thioguanine nucleotides (TGN).…”

Biomarkers for gastrointestinal adverse events related to thiopurine therapy

“…twice a week for 2 wk at SJRCH, whereas those undergoing the AIEOP-BFM 2000 protocol were treated daily with 25 mg/m 2 MP and received four HD-MTX (2-5 g/m 2 ) infusions once every 2 wk. To further validate these results, Franca et al [ 33 ] investigated the possible role of PACSIN2 rs2413739 in an additional cohort of ALL pediatric patients treated according to the AIEOP-BFM 2009 protocol, with the same consolidation phase as AIEOP-BFM ALL 2000, and in a cohort of IBD pediatric patients undergoing AZA therapy. In the ALL cohort, the PACSIN2 T allele was associated with decreased TPMT activity during maintenance therapy, particularly in patients heterozygous for TPMT rs1142345 and rs1800460.…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“…Other SNPs that have been studied in relation to thiopurine sensitivity are variants within the phosphoribosylglycinamide formyltransferase (GART) gene (involved in folate cycle), Molybdenum Cofactor Sulfurase (MOCOS) gene (involved in thiopurine metabolism) and Protein Kinase C And Casein Kinase Substrate In Neurons 2 (PACSIN2) gene (involved in thiopurine metabolism (Smid et al, 2016;Franca et al, 2019). Polymorphisms in PACSIN2 have been associated with an increased risk of GI and hematologic toxicity during 6MP treatment.…”

“…TPMP activity is well studied and shown to be highly variable among individuals, although the incidence of genetic variants differs between ethnic populations ( Jimenez-Morales et al., 2016 ). In Caucasians, 90% to 95% of subjects have a normal/high TPMT activity, 5% to 10% reduced and around 0.5% an absent enzymatic activity ( Franca et al., 2019 ). In Asian and Hispanic population, the incidence of variant TPMT genes is much lower ( Koutsilieri et al., 2019 ).…”