Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia

TY - JOUR

T1 - Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia

T2 - a Ponte di Legno toxicity working group report

AU - Wolthers, Benjamin O

AU - Frandsen, Thomas L

AU - Patel, Chirag J

AU - Abaji, Rachid

AU - Attarbaschi, Andishe

AU - Barzilai, Shlomit

AU - Colombini, Antonella

AU - Escherich, Gabriele

AU - Grosjean, Marie

AU - Krajinovic, Maja

AU - Larsen, Eric

AU - Liang, Der-Cherng

AU - Möricke, Anja

AU - Rasmussen, Kirsten K

AU - Samarasinghe, Sujith

AU - Silverman, Lewis B

AU - van der Sluis, Inge M

AU - Stanulla, Martin

AU - Tulstrup, Morten

AU - Yadav, Rachita

AU - Yang, Wenjian

AU - Zapotocka, Ester

AU - Gupta, Ramneek

AU - Schmiegelow, Kjeld

N1 - Copyright© 2019 Ferrata Storti Foundation.

PY - 2019/3

Y1 - 2019/3

N2 - 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 (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.

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 (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.

KW - Journal Article

U2 - 10.3324/haematol.2018.199356

DO - 10.3324/haematol.2018.199356

M3 - SCORING: Journal article

C2 - 30467200

VL - 104

SP - 556

EP - 563

JO - HAEMATOLOGICA

JF - HAEMATOLOGICA

SN - 0390-6078

IS - 3

ER -