Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia

Chengcheng Liu, Wenjian Yang, Meenakshi Devidas, Cheng Cheng, Deqing Pei, Colton Smith, William L. Carroll, Elizabeth A. Raetz, W. Paul Bowman, Eric C. Larsen, Kelly W. Maloney, Paul L. Martin, Leonard A. Mattano, Naomi J. Winick, Elaine R. Mardis, Robert S. Fulton, Deepa Bhojwani, Scott Howard, Sima Jeha, Ching Hon Pui & 4 others Stephen P. Hunger, William E. Evans, Mignon L. Loh, Mary V. Relling

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2133-2140
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number18
DOIs
StatePublished - Jun 20 2016

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pancreatitis
Asparaginase
North American Indians
Genome-Wide Association Study
Carboxypeptidases A
Genetic Predisposition to Disease
Cytoskeleton
Genes
Single Nucleotide Polymorphism
Young Adult
Genome
Control Groups

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia. / Liu, Chengcheng; Yang, Wenjian; Devidas, Meenakshi; Cheng, Cheng; Pei, Deqing; Smith, Colton; Carroll, William L.; Raetz, Elizabeth A.; Bowman, W. Paul; Larsen, Eric C.; Maloney, Kelly W.; Martin, Paul L.; Mattano, Leonard A.; Winick, Naomi J.; Mardis, Elaine R.; Fulton, Robert S.; Bhojwani, Deepa; Howard, Scott; Jeha, Sima; Pui, Ching Hon; Hunger, Stephen P.; Evans, William E.; Loh, Mignon L.; Relling, Mary V.

In: Journal of Clinical Oncology, Vol. 34, No. 18, 20.06.2016, p. 2133-2140.

Research output: Contribution to journalArticle

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, S, Jeha, S, Pui, CH, Hunger, SP, Evans, WE, Loh, ML & Relling, MV 2016, 'Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia', Journal of Clinical Oncology, vol. 34, no. 18, pp. 2133-2140. https://doi.org/10.1200/JCO.2015.64.5812
Liu, Chengcheng ; Yang, Wenjian ; Devidas, Meenakshi ; Cheng, Cheng ; Pei, Deqing ; Smith, Colton ; Carroll, William L. ; Raetz, Elizabeth A. ; Bowman, W. Paul ; Larsen, Eric C. ; Maloney, Kelly W. ; Martin, Paul L. ; Mattano, Leonard A. ; Winick, Naomi J. ; Mardis, Elaine R. ; Fulton, Robert S. ; Bhojwani, Deepa ; Howard, Scott ; Jeha, Sima ; Pui, Ching Hon ; Hunger, Stephen P. ; Evans, William E. ; Loh, Mignon L. ; Relling, Mary V. / Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia. In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 18. pp. 2133-2140.
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title = "Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia",
abstract = "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.",
author = "Chengcheng Liu and Wenjian Yang and Meenakshi Devidas and Cheng Cheng and Deqing Pei and Colton Smith and Carroll, {William L.} and Raetz, {Elizabeth A.} and Bowman, {W. Paul} and Larsen, {Eric C.} and Maloney, {Kelly W.} and Martin, {Paul L.} and Mattano, {Leonard A.} and Winick, {Naomi J.} and Mardis, {Elaine R.} and Fulton, {Robert S.} and Deepa Bhojwani and Scott Howard and Sima Jeha and Pui, {Ching Hon} and Hunger, {Stephen P.} and Evans, {William E.} and Loh, {Mignon L.} and Relling, {Mary V.}",
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T1 - Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia

AU - Liu, Chengcheng

AU - Yang, Wenjian

AU - Devidas, Meenakshi

AU - Cheng, Cheng

AU - Pei, Deqing

AU - Smith, Colton

AU - Carroll, William L.

AU - Raetz, Elizabeth A.

AU - Bowman, W. Paul

AU - Larsen, Eric C.

AU - Maloney, Kelly W.

AU - Martin, Paul L.

AU - Mattano, Leonard A.

AU - Winick, Naomi J.

AU - Mardis, Elaine R.

AU - Fulton, Robert S.

AU - Bhojwani, Deepa

AU - Howard, Scott

AU - Jeha, Sima

AU - Pui, Ching Hon

AU - Hunger, Stephen P.

AU - Evans, William E.

AU - Loh, Mignon L.

AU - Relling, Mary V.

PY - 2016/6/20

Y1 - 2016/6/20

N2 - 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.

AB - 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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U2 - 10.1200/JCO.2015.64.5812

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