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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.
SUBMITTER: Liu C
PROVIDER: S-EPMC4962704 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Liu Chengcheng C Yang Wenjian W Devidas Meenakshi M Cheng Cheng C Pei Deqing D Smith Colton C Carroll William L WL Raetz Elizabeth A EA Bowman W Paul WP Larsen Eric C EC Maloney Kelly W KW Martin Paul L PL Mattano Leonard A LA Winick Naomi J NJ Mardis Elaine R ER Fulton Robert S RS Bhojwani Deepa D Howard Scott C SC Jeha Sima S Pui Ching-Hon CH Hunger Stephen P SP Evans William E WE Loh Mignon L ML Relling Mary V MV
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20160425 18
<h4>Purpose</h4>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.<h4>Methods</h4>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. ...[more]