Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report
Benjamin O. Wolthers,
Thomas L. Frandsen,
Chirag J. Patel,
Rachid Abaji,
Andishe Attarbaschi,
Shlomit Barzilai,
Antonella Colombini,
Gabriele Escherich,
Marie Grosjean,
Maja Krajinovic,
Eric Larsen,
Der-Cherng Liang,
Anja Möricke,
Kirsten K. Rasmussen,
Sujith Samarasinghe,
Lewis B. Silverman,
Inge M. van der Sluis,
Martin Stanulla,
Morten Tulstrup,
Rachita Yadav,
Wenjian Yang,
Ester Zapotocka,
Ramneek Gupta,
Kjeld Schmiegelow
Affiliations
Benjamin O. Wolthers
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
Thomas L. Frandsen
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
Chirag J. Patel
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
Rachid Abaji
CHU Sainte-Justine Research Center and Department of Pharmacology, University of Montreal, QC, Canada
Andishe Attarbaschi
Department of Pediatric Hematology and Oncology, St Anna Children’s Hospital and Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Austria
Shlomit Barzilai
Pediatric Hematology and Oncology, Schneider Children’s Medical Center of Israel, Petah-Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Israel
Antonella Colombini
Department of Pediatrics, Ospedale San Gerardo, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy
Gabriele Escherich
University Medical Center Eppendorf, Clinic of Pediatric Hematology and Oncology, Hamburg, Germany
Marie Grosjean
Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark
Maja Krajinovic
CHU Sainte-Justine Research Center and Department of Pharmacology, University of Montreal, QC, Canada;Department of Pediatrics, University of Montreal, QC, Canada
Eric Larsen
Maine Children’s Cancer Program, Scarborough, ME, USA
Der-Cherng Liang
Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan
Anja Möricke
Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Department of Pediatrics, Kiel, Germany
Kirsten K. Rasmussen
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
Sujith Samarasinghe
Great Ormond Street Hospital for Children, London, UK
Lewis B. Silverman
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA
Inge M. van der Sluis
Dutch Childhood Oncology Group, The Hague and Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Martin Stanulla
Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany
Morten Tulstrup
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark
Rachita Yadav
Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark;Molecular Neurogenetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Wenjian Yang
St. Jude Children’s Research Hospital, Department of Pharmaceutical Sciences, Memphis, TN, USA
Ester Zapotocka
University Hospital Motol, Department of Pediatric Hematology/Oncology, Prague, Czech Republic
Ramneek Gupta
Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark
Kjeld Schmiegelow
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark;Institute of Clinical Medicine, University of Copenhagen, Denmark
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.
