title: Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol.
abstract: Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence=6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting >72 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P=0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P=5.8 × 10-7; odds ratio (OR)=6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P=0.015) and had lower risk of AAP-related complications (15% vs 43%; P=0.13) compared with cases without this variant. Among 45 cases and 517 controls <10 years, the strongest associations with AAP were found for RGS6 variant rs17179470 (P=9.8 × 10-9; OR=7.3). Rs281366 is located in the ULK2 gene involved in autophagy, and RGS6 regulates G-protein signaling regulating cell dynamics. More than 50% of AAP cases <10 years carried one or both risk alleles.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: B O
authors.initials: BO
authors.lastname: Wolthers
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: T L
authors.initials: TL
authors.lastname: Frandsen
authors.affiliation: Department of Clinical Sciences, Queen Silvia's Children's Hospital, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Abrahamsson
authors.affiliation: Department of Paediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark.
authors.forename: B K
authors.initials: BK
authors.lastname: Albertsen
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: L R
authors.initials: LR
authors.lastname: Helt
authors.affiliation: Department of Pediatrics, Astrid Lindgrens Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Heyman
authors.affiliation: Children's Hospital, Landspitali University Hospital, Reykjavík, Iceland.
authors.forename: Ó G
authors.initials: ÓG
authors.lastname: Jónsson
authors.affiliation: Tartu University Hospital, Tartu, Estonia.
authors.forename: L T
authors.initials: LT
authors.lastname: Kõrgvee
authors.affiliation: Department of Paediatrics, St Olavs University Hospital, Trondheim, Norway.|Department of Laboratory Medicine, Children's and Women's Health, Medical Faculty, The Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Lund
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: R A
authors.initials: RA
authors.lastname: Raja
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: K K
authors.initials: KK
authors.lastname: Rasmussen
authors.affiliation: Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Taskinen
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Tulstrup
authors.affiliation: Clinic of Children's Diseases, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
authors.forename: G E
authors.initials: GE
authors.lastname: Vaitkevičienė
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Yadav
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.|Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Schmiegelow
mesh_terms: D000293:Adolescent; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001215:Asparaginase / Q000009:adverse effects* / Q000627:therapeutic use; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D016017:Odds Ratio; D010195:Pancreatitis / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D017346:Protein Serine-Threonine Kinases; C541703:Ulk2 protein, human; D001215:Asparaginase