Abstract
| Original language | English |
|---|---|
| Journal | Haematologica |
| Volume | 104 |
| Issue number | 3 |
| Pages (from-to) | 556-563 |
| Number of pages | 8 |
| ISSN | 0390-6078 |
| DOIs | |
| Publication status | Published - 2019 |
Cite this
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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. / 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.
In: Haematologica, Vol. 104, No. 3, 2019, p. 556-563.Research output: Contribution to journal › Journal article › Research › peer-review
TY - JOUR
T1 - 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
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
PY - 2019
Y1 - 2019
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 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.
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 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.
U2 - 10.3324/haematol.2018.199356
DO - 10.3324/haematol.2018.199356
M3 - Journal article
C2 - 30467200
VL - 104
SP - 556
EP - 563
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 3
ER -