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 Larse N, Der Cherng Liang, Anja Möricke, Kirsten K. Rasmussen, Sujith Samarasinghe, Lewis B. Silverman, Inge M. van der Sluis, Martin Stanulla, Morten Tulstrup, Rachita YadavWenjian Yang, Ester Zapotocka, Ramneek Gupta, Kjeld Schmiegelow

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

22 Citaten (Scopus)

Samenvatting

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 x 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=5.2x10 -8 ). Moreover, rs13228878 (OR=0.61; P=7.1x10 -6 ) and rs10273639 (OR=0.62; P=1.1x10 -5 ) on 7q34 showed significant association 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 (r 2 =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.

Originele taal-2Engels
Pagina's (van-tot)556-563
Aantal pagina's8
TijdschriftHaematologica
Volume104
Nummer van het tijdschrift3
DOI's
StatusGepubliceerd - 28 feb. 2019

Vingerafdruk

Duik in de onderzoeksthema's van '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'. Samen vormen ze een unieke vingerafdruk.

Citeer dit