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

被引：88

作者：

Liu, Chengcheng ^{[1
]}

Yang, Wenjian ^{[1
]}

Devidas, Meenakshi ^{[3
]}

Cheng, Cheng ^{[1
]}

Pei, Deqing ^{[1
]}

Smith, Colton ^{[1
]}

Carroll, William L. ^{[4
]}

Raetz, Elizabeth A. ^{[5
]}

Bowman, W. Paul ^{[6
]}

Larsen, Eric C. ^{[8
]}

Maloney, Kelly W. ^{[9
]}

Martin, Paul L. ^{[10
]}

Mattano, Leonard A., Jr. ^{[11
]}

Winick, Naomi J. ^{[7
]}

Mardis, Elaine R. ^{[12
]}

Fulton, Robert S. ^{[12
]}

Bhojwani, Deepa ^{[13
]}

Howard, Scott C. ^{[2
]}

Jeha, Sima ^{[1
]}

Pui, Ching-Hon ^{[1
]}

Hunger, Stephen P. ^{[15
]}

Evans, William E. ^{[1
]}

Loh, Mignon L. ^{[14
]}

Relling, Mary V. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[2] Univ Memphis, Memphis, TN 38152 USA

[3] Univ Florida, Gainesville, FL USA

[4] NYU, Langone Med Ctr, New York, NY USA

[5] Univ Utah, Salt Lake City, UT USA

[6] Cook Childrens Hosp, Ft Worth, TX USA

[7] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA

[8] Maine Childrens Canc Program, Scarborough, ME USA

[9] Univ Colorado Denver, Aurora, CO USA

[10] Duke Univ, Durham, NC USA

[11] HARP Pharma Consulting, Mystic, CT USA

[12] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA

[13] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA

[14] Univ Calif San Francisco, Med Ctr Parnassus, San Francisco, CA 94143 USA

[15] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2016年 / 34卷 / 18期

关键词：

MINIMAL RESIDUAL DISEASE; ASPARAGINASE-ASSOCIATED PANCREATITIS; CALCIUM-SENSING RECEPTOR; COLI ASPARAGINASE; STANDARD-RISK; CHILDREN; MUTATIONS; VARIANTS; PROTOCOL; ASSOCIATION;

D O I：

10.1200/JCO.2015.64.5812

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 x 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. (C) 2016 by American Society of Clinical Oncology

引用

页码：2133 / +

页数：9

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