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

38 Citations (Scopus)

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

Fingerprint

thiopurine methyltransferase
Casein Kinases
6-Mercaptopurine
Neurons
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Single Nucleotide Polymorphism
HapMap Project
Therapeutics
protein kinase C kinase
Cell Line
Messenger RNA
Genetic Polymorphisms
Clinical Protocols

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Stocco, G., Yang, W., Crews, K. R., Thierfelder, W. E., Decorti, G., Londero, M., ... 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

PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. / Stocco, Gabriele; Yang, Wenjian; Crews, Kristine R.; Thierfelder, William E.; Decorti, Giuliana; Londero, Margherita; Franca, Raffaella; Rabusin, Marco; Valsecchi, Maria Grazia; Pei, Deqing; Cheng, Cheng; Paugh, Steven W.; Ramsey, Laura B.; Diouf, Barthelemy; Mccorkle, Joseph Robert; Jones, Terreia S.; Pui, Ching Hon; Relling, Mary V.; Evans, William E.

In: Human Molecular Genetics, Vol. 21, No. 21, dds302, 11.2012, p. 4793-4804.

Research output: Contribution to journalArticle

Stocco, G, Yang, W, Crews, KR, Thierfelder, WE, Decorti, G, Londero, M, Franca, R, Rabusin, M, Valsecchi, MG, Pei, D, Cheng, C, Paugh, SW, Ramsey, LB, Diouf, B, Mccorkle, JR, Jones, TS, Pui, CH, Relling, MV & Evans, WE 2012, 'PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity', Human Molecular Genetics, vol. 21, no. 21, dds302, pp. 4793-4804. https://doi.org/10.1093/hmg/dds302
Stocco G, Yang W, Crews KR, Thierfelder WE, Decorti G, Londero M et al. PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. Human Molecular Genetics. 2012 Nov;21(21):4793-4804. dds302. https://doi.org/10.1093/hmg/dds302
Stocco, Gabriele ; Yang, Wenjian ; Crews, Kristine R. ; Thierfelder, William E. ; Decorti, Giuliana ; Londero, Margherita ; Franca, Raffaella ; Rabusin, Marco ; Valsecchi, Maria Grazia ; Pei, Deqing ; Cheng, Cheng ; Paugh, Steven W. ; Ramsey, Laura B. ; Diouf, Barthelemy ; Mccorkle, Joseph Robert ; Jones, Terreia S. ; Pui, Ching Hon ; Relling, Mary V. ; Evans, William E. / PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 21. pp. 4793-4804.
@article{ab726dd8d0db4a669d3b1a17530d19e8,
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.",
author = "Gabriele Stocco and Wenjian Yang and Crews, {Kristine R.} and Thierfelder, {William E.} and Giuliana Decorti and Margherita Londero and Raffaella Franca and Marco Rabusin and Valsecchi, {Maria Grazia} and Deqing Pei and Cheng Cheng and Paugh, {Steven W.} and Ramsey, {Laura B.} and Barthelemy Diouf and Mccorkle, {Joseph Robert} and Jones, {Terreia S.} and Pui, {Ching Hon} and Relling, {Mary V.} and Evans, {William E.}",
year = "2012",
month = "11",
doi = "10.1093/hmg/dds302",
language = "English",
volume = "21",
pages = "4793--4804",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "21",

}

TY - JOUR

T1 - PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity

AU - Stocco, Gabriele

AU - Yang, Wenjian

AU - Crews, Kristine R.

AU - Thierfelder, William E.

AU - Decorti, Giuliana

AU - Londero, Margherita

AU - Franca, Raffaella

AU - Rabusin, Marco

AU - Valsecchi, Maria Grazia

AU - Pei, Deqing

AU - Cheng, Cheng

AU - Paugh, Steven W.

AU - Ramsey, Laura B.

AU - Diouf, Barthelemy

AU - Mccorkle, Joseph Robert

AU - Jones, Terreia S.

AU - Pui, Ching Hon

AU - Relling, Mary V.

AU - Evans, William E.

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867788966&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867788966&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds302

DO - 10.1093/hmg/dds302

M3 - Article

C2 - 22846425

AN - SCOPUS:84867788966

VL - 21

SP - 4793

EP - 4804

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 21

M1 - dds302

ER -