Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0-17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2×10-8). Moreover, rs13228878 (OR=0.61; P=7.1×10-6) and rs10273639 (OR=0.62; P=1.1×10-5) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.

Center for Biological Sequence Analysis Technical University of Denmark Lyngby Denmark

Christian Albrechts University Kiel and University Medical Center Schleswig Holstein Department of Pediatrics Kiel Germany

CHU Sainte Justine Research Center and Department of Pharmacology University of Montreal QC Canada

Department of Biomedical Informatics Harvard Medical School Boston MA USA

Department of Pediatric Hematology and Oncology Hannover Medical School Germany

Department of Pediatric Hematology and Oncology St Anna Children's Hospital and Department of Pediatric and Adolescent Medicine Medical University of Vienna Austria

Department of Pediatric Oncology Dana Farber Cancer Institute and Division of Hematology Oncology Boston Children's Hospital Boston MA USA

Department of Pediatrics and Adolescent Medicine University Hospital Rigshospitalet Copenhagen Denmark

Department of Pediatrics Ospedale San Gerardo University of Milano Bicocca Fondazione MBBM Monza Italy

Department of Pediatrics University of Montreal QC Canada

Division of Pediatric Hematology Oncology Mackay Memorial Hospital Taipei Taiwan

Dutch Childhood Oncology Group The Hague and Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

Great Ormond Street Hospital for Children London UK

Institute of Clinical Medicine University of Copenhagen Denmark

Maine Children's Cancer Program Scarborough ME USA

Molecular Neurogenetics Unit Psychiatric and Neurodevelopmental Genetics Unit Center for Genomic Medicine Massachusetts General Hospital Boston MA USA

Pediatric Hematology and Oncology Schneider Children's Medical Center of Israel Petah Tikva Israel and Sackler Faculty of Medicine Tel Aviv University Israel

St Jude Children's Research Hospital Department of Pharmaceutical Sciences Memphis TN USA

University Hospital Motol Department of Pediatric Hematology Oncology Prague Czech Republic

University Medical Center Eppendorf Clinic of Pediatric Hematology and Oncology Hamburg Germany

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Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia