PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity

Gabriele Stocco, Wenjian Yang, Kristine R. Crews, William E. Thierfelder, Giuliana Decorti, Margherita Londero, Raffaella Franca, Marco Rabusin, Maria Grazia Valsecchi, Deqing Pei, Cheng Cheng, Steven W. Paugh, Laura B. Ramsey, Barthelemy Diouf, Joseph Robert Mccorkle, Terreia S. Jones, Ching Hon Pui, Mary V. Relling, William E. Evans

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numberdds302
Pages (from-to)4793-4804
Number of pages12
JournalHuman Molecular Genetics
Volume21
Issue number21
DOIs
Publication statusPublished - Nov 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Stocco, G., Yang, W., Crews, K. R., Thierfelder, W. E., Decorti, G., Londero, M., Franca, R., Rabusin, M., Valsecchi, M. G., Pei, D., Cheng, C., Paugh, S. W., Ramsey, L. B., Diouf, B., Mccorkle, J. R., Jones, T. S., Pui, C. H., Relling, M. V., & Evans, W. E. (2012). PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. Human Molecular Genetics, 21(21), 4793-4804. [dds302]. https://doi.org/10.1093/hmg/dds302