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

• Published in: Haematologica (Roma) 2019-03, Vol.104 (3), p.556-563
• Main Authors: Wolthers, Benjamin O, Frandsen, Thomas L, Patel, Chirag J, Abaji, Rachid, Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Grosjean, Marie, Krajinovic, Maja, Larsen, Eric, Liang, Der-Cherng, Möricke, Anja, Rasmussen, Kirsten K, Samarasinghe, Sujith, Silverman, Lewis B, van der Sluis, Inge M, Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Yang, Wenjian, Zapotocka, Ester, Gupta, Ramneek, Schmiegelow, Kjeld
• Format: Article
• Language: English
• Subjects: Adolescent; Alleles; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Asparaginase - administration & dosage; Asparaginase - adverse effects; Child; Child, Preschool; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Infant; Male; Models, Biological; Pancreatitis - etiology; Phenotype; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - adverse effects; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Trypsin - genetics; Trypsinogen - genetics
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2018.199356

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; =5.2×10 ). Moreover, rs13228878 (OR=0.61; =7.1×10 ) and rs10273639 (OR=0.62; =1.1×10 ) 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 ( =0.77), both rs13228878 ( =0.03) and rs10273639 ( =0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r =0.94) and associated with elevated expression of the 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.