title: PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity.
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.
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Gabriele
authors: G
authors: Stocco
authors: Wenjian
authors: W
authors: Yang
authors: Kristine R
authors: KR
authors: Crews
authors: William E
authors: WE
authors: Thierfelder
authors: Giuliana
authors: G
authors: Decorti
authors: Margherita
authors: M
authors: Londero
authors: Raffaella
authors: R
authors: Franca
authors: Marco
authors: M
authors: Rabusin
authors: Maria Grazia
authors: MG
authors: Valsecchi
authors: Deqing
authors: D
authors: Pei
authors: Cheng
authors: C
authors: Cheng
authors: Steven W
authors: SW
authors: Paugh
authors: Laura B
authors: LB
authors: Ramsey
authors: Barthelemy
authors: B
authors: Diouf
authors: Joseph Robert
authors: JR
authors: McCorkle
authors: Terreia S
authors: TS
authors: Jones
authors: Ching-Hon
authors: CH
authors: Pui
authors: Mary V
authors: MV
authors: Relling
authors: William E
authors: WE
authors: Evans
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D005260:Female; D041981:Gastrointestinal Tract / Q000503:physiopathology; D015870:Gene Expression; D055106:Genome-Wide Association Study; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120714:PACSIN2 protein, human; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase