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  • Author: Wolthers, Benjamin Ole

    Righospitalet , Denmark

  • Author: Frandsen, Thomas L.

    Righospitalet , Denmark

  • Author: Patel, Chirag J

    Harvard Medical School, United States

  • Author: Abaji, Rachid

    University of Montreal, Canada

  • Author: Attarbaschi, Andishe

    Medical University of Vienna, Austria

  • Author: Barzilai, Shlomit

    Tel Aviv University, Israel

  • Author: Colombini, Antonella

    University of Milan - Bicocca, Italy

  • Author: Escherich, Gabriele

    University Medical Center Hamburg-Eppendorf, Germany

  • Author: Grosjean, Marie

    Department of Health Technology, Technical University of Denmark

  • Author: Krajinovic, Maja

    University of Montreal, Canada

  • Author: Larsen, Eric

    Maine Children's Cancer Program, United States

  • Author: Liang, Der-Cherng

    Mackay Memorial Hospital Taiwan, Taiwan, Province of China

  • Author: Möricke, Anja

    Christian Albrechts University of Kiel, Germany

  • Author: Rasmussen, Kirsten Kørup

    Righospitalet , Denmark

  • Author: Samarasinghe, Sujith

    Great Ormond Street Hospital for Children, United States

  • Author: Silverman, Lewis B.

    Boston Children’s Hospital, United States

  • Author: van der Sluis, Inge M.

    Erasmus University Medical Center, Netherlands

  • Author: Stanulla, Martin

    Hannover Medical School, Germany

  • Author: Tulstrup, Morten

    Righospitalet , Denmark

  • Author: Yadav, Rachita

    Department of Health Technology, Technical University of Denmark

  • Author: Yang, Wenjian

    St Jude Children's Research Hospital

  • Author: Zapotocka, Ester

    University Hospital Motol, Czech Republic

  • Author: Gupta, Ramneek

    Disease Data Intelligence, Bioinformatics, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800, Kgs. Lyngby, Denmark

  • Author: Schmiegelow, Kjeld

    Righospitalet , Denmark

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Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten acute lymphoblastic leukemia trial groups contributed remission samples from patients aged 1.0-17.9 years and treated from 2000-2016. Cases were defined (n=244) by at least two of the following criteria: i) abdominal pain, ii) pancreatic enzymes >3 x upper normal limit, iii) imaging compatible with asparaginase-associated pancreatitis. Controls (n=1320) completed intended asparaginase therapy, 78% receiving ≥8 pegylated-asparaginase injections, without developing aparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association (OR=3.75; P=5.2x10-8). Moreover, rs13228878 (OR=0.61; P=7.1x10-6) and rs10273639 (OR=0.62; P=1.1x10-5) on 7q34 showed significant association. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated protocols from 1987-2004 (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 (P=0.86), 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 trypsinogen encoding PRSS1 gene and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. Asparaginase-associated pancreatitis and non-asparaginase associated pancreatitis shares genetic predisposition and targeting the trypsinogen activation pathway may enable identification of effective interventions towards asparaginase-associated pancreatitis.
Original languageEnglish
JournalHaematologica
Volume104
Issue number3
Pages (from-to)556-563
Number of pages8
ISSN0390-6078
DOIs
Publication statusPublished - 2019
CitationsWeb of Science® Times Cited: No match on DOI

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