ArticleHuman molecular genetics2012
PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00137111 (Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia), which is not on this map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
- Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies.Clinical pharmacology and therapeutics · 2017Pooled it
- PACSIN2 rs2413739 influence on thiopurine pharmacokinetics: validation studies in pediatric patients.The pharmacogenomics journal · 2020Trial
- Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort.Scientific reports · 2016Trial
- Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes.Pharmacogenomics · 2014Trial
- Exploring the gut microbiome and metabolomic interactions of antimetabolite drugs to optimize therapy.Gut microbes · 2026Review
- Personalized Therapy with Mercaptopurine in Acute Lymphoblastic Leukemia: Current Advances and Challenges.Current treatment options in oncology · 2026Review
- Association of Variants in Candidate Pharmacogenes with Response to Mercaptopurine and Methotrexate in Pediatric Acute Lymphoblastic Leukemia: A Single-Center Experience from Croatia.Oncology and therapy · 2026Article
- Population frequencies of thiopurine-related pharmacogenes in healthy individuals from Kosovo.Human genome variation · 2026Article
- Pharmacogenomics Applied to Acute Leukemias: Identifying Clinically Relevant Genetic Variants.Biomedicines · 2025Review
- Azathioprine Metabolites in Erythrocytes and DNA for Therapy Monitoring in Very Early Onset Inflammatory Bowel Disease Pediatric Patients.ACS pharmacology & translational science · 2025Article
- Article
- Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia.Cancer medicine · 2022Article
- PACSIN proteins in vivo: Roles in development and physiology.Acta physiologica (Oxford, England) · 2022Review
- Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising "MINT" sequencing strategy and therapeutic "DNA-TG" monitoring.Frontiers in pharmacology · 2022Review
- Biomarkers for gastrointestinal adverse events related to thiopurine therapy.World journal of gastroenterology · 2021Article
- Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism.Basic & clinical pharmacology & toxicology · 2021Review
- Childhood acute lymphoblastic leukemia mercaptopurine intolerance is associated with NUDT15 variants.Pediatric research · 2021Article
- Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants.Frontiers in genetics · 2021Article
- Association between theGenes · 2020Article
- The Roles of Common Variation and Somatic Mutation in Cancer Pharmacogenomics.Oncology and therapy · 2019Review
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Authors and funding
19 authors at 7 institutions in 3 countries.
Funding
Abstract
Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single-nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.