Journal article
Trypsin encoding PRSS1-PRSS2 variation influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report
Rigshospitalet1
Mackay Memorial Hospital Taiwan2
Christian Albrechts University of Kiel3
Great Ormond Street Hospital for Children4
Boston Children's Hospital5
Erasmus University Medical Center6
Hannover Medical School7
St. Jude Children’s Research Hospital8
University Hospital Motol9
Disease Data Intelligence, Bioinformatics, Department of Health Technology, Technical University of Denmark10
Bioinformatics, Department of Health Technology, Technical University of Denmark11
Massachusetts General Hospital/Harvard Medical School12
University of Montreal13
Medical University of Vienna14
Tel Aviv University15
University of Milan - Bicocca16
University Medical Center Hamburg-Eppendorf17
Department of Health Technology, Technical University of Denmark18
Maine Children's Cancer Program19
...and 9 moreAsparaginase-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.
Language: | English |
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Publisher: | Ferrata Storti Foundation |
Year: | 2019 |
Pages: | 556-563 |
ISSN: | 15928721 and 03906078 |
Types: | Journal article |
DOI: | 10.3324/haematol.2018.199356 |
ORCIDs: | Gupta, Ramneek |
Adolescent Alleles Antineoplastic Agents Asparaginase Child Child, Preschool Female Genetic Association Studies Genetic Predisposition to Disease Genetic Variation Genotype Humans Infant Male Models, Biological PRSS1 protein, human PRSS2 protein, human Pancreatitis Phenotype Polyethylene Glycols Polymorphism, Single Nucleotide Precursor Cell Lymphoblastic Leukemia-Lymphoma Trypsin Trypsinogen pegaspargase