TY - JOUR AU - Benjamin O. Wolthers, AU - Thomas L. Frandsen, AU - Chirag J. Patel, AU - Rachid Abaji, AU - Andishe Attarbaschi, AU - Shlomit Barzilai, AU - Antonella Colombini, AU - Gabriele Escherich, AU - Marie Grosjean, AU - Maja Krajinovic, AU - Eric Larsen, AU - Der-Cherng Liang, AU - Anja Möricke, AU - Kirsten K. Rasmussen, AU - Sujith Samarasinghe, AU - Lewis B. Silverman, AU - Inge M. van der Sluis, AU - Martin Stanulla, AU - Morten Tulstrup, AU - Rachita Yadav, AU - Wenjian Yang, AU - Ester Zapotocka, AU - Ramneek Gupta, AU - Kjeld Schmiegelow, PY - 2019/02/28 Y2 - 2024/03/28 TI - 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 JF - Haematologica JA - haematol VL - 104 IS - 3 SE - Articles DO - 10.3324/haematol.2018.199356 UR - https://haematologica.org/article/view/8813 SP - 556-563 AB - 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. ER -