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Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia.

Publication ,  Journal Article
Liu, C; Yang, W; Devidas, M; Cheng, C; Pei, D; Smith, C; Carroll, WL; Raetz, EA; Bowman, WP; Larsen, EC; Maloney, KW; Martin, PL; Mattano, LA ...
Published in: J Clin Oncol
June 20, 2016

PURPOSE: Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. METHODS: To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. RESULTS: Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10(-9)). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. CONCLUSION: Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.

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Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

June 20, 2016

Volume

34

Issue

18

Start / End Page

2133 / 2140

Location

United States

Related Subject Headings

  • Risk Factors
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Pancreatitis
  • Oncology & Carcinogenesis
  • Infant, Newborn
  • Infant
  • Humans
  • Genome-Wide Association Study
  • Child, Preschool
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Liu, C., Yang, W., Devidas, M., Cheng, C., Pei, D., Smith, C., … Relling, M. V. (2016). Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia. J Clin Oncol, 34(18), 2133–2140. https://doi.org/10.1200/JCO.2015.64.5812
Liu, Chengcheng, Wenjian Yang, Meenakshi Devidas, Cheng Cheng, Deqing Pei, Colton Smith, William L. Carroll, et al. “Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia.J Clin Oncol 34, no. 18 (June 20, 2016): 2133–40. https://doi.org/10.1200/JCO.2015.64.5812.
Liu C, Yang W, Devidas M, Cheng C, Pei D, Smith C, et al. Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Jun 20;34(18):2133–40.
Liu, Chengcheng, et al. “Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia.J Clin Oncol, vol. 34, no. 18, June 2016, pp. 2133–40. Pubmed, doi:10.1200/JCO.2015.64.5812.
Liu C, Yang W, Devidas M, Cheng C, Pei D, Smith C, Carroll WL, Raetz EA, Bowman WP, Larsen EC, Maloney KW, Martin PL, Mattano LA, Winick NJ, Mardis ER, Fulton RS, Bhojwani D, Howard SC, Jeha S, Pui C-H, Hunger SP, Evans WE, Loh ML, Relling MV. Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Jun 20;34(18):2133–2140.

Published In

J Clin Oncol

DOI

EISSN

1527-7755

Publication Date

June 20, 2016

Volume

34

Issue

18

Start / End Page

2133 / 2140

Location

United States

Related Subject Headings

  • Risk Factors
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Pancreatitis
  • Oncology & Carcinogenesis
  • Infant, Newborn
  • Infant
  • Humans
  • Genome-Wide Association Study
  • Child, Preschool