Chengcheng Liu1, Wenjian Yang1, Meenakshi Devidas1, Cheng Cheng1, Deqing Pei1, Colton Smith1, William L Carroll1, Elizabeth A Raetz1, W Paul Bowman1, Eric C Larsen1, Kelly W Maloney1, Paul L Martin1, Leonard A Mattano1, Naomi J Winick1, Elaine R Mardis1, Robert S Fulton1, Deepa Bhojwani1, Scott C Howard1, Sima Jeha1, Ching-Hon Pui1, Stephen P Hunger1, William E Evans1, Mignon L Loh1, Mary V Relling2. 1. Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA. 2. Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA. mary.relling@stjude.org.
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.
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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