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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.

ABSTRACT: 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.

SUBMITTER: Wolthers BO

PROVIDER: S-EPMC6395330 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Trypsin-encoding <i>PRSS1-PRSS2</i> variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report.

Wolthers Benjamin O BO Frandsen Thomas L TL Patel Chirag J CJ Abaji Rachid R Attarbaschi Andishe A Barzilai Shlomit S Colombini Antonella A Escherich Gabriele G Grosjean Marie M Krajinovic Maja M Larsen Eric E Liang Der-Cherng DC Möricke Anja A Rasmussen Kirsten K KK Samarasinghe Sujith S Silverman Lewis B LB van der Sluis Inge M IM Stanulla Martin M Tulstrup Morten M Yadav Rachita R Yang Wenjian W Zapotocka Ester E Gupta Ramneek R Schmiegelow Kjeld K

Haematologica 20181122 3

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 ...[more]

PMID: 30467200

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Project description:Background and Aim:The risks of post-ERCP pancreatitis (PEP) are identified as patient- and procedure-related factors. However, the genetic contribution for PEP is still unclear. Recent data show that the polymorphisms of PRSS1-PRSS2 (rs10273639) and MORC4 (rs12688220) are associated with recurrent acute pancreatitis and chronic pancreatitis. We aim to evaluate the association between these polymorphisms and post-ERCP pancreatitis in order to improve better prognosis and better care for these patients. Methods:This is a retrospective, case-control study which includes 49 cases and 97 controls that are age-, procedure-, and risk of PEP-matched with the cases in 1?:?2 fashion. The PEP was diagnosed and graded for severity according to the standard consensus, and the risk factors of PEP were identified according to the ESGE guideline. Polymorphisms at rs10273639 and rs12688220 were evaluated by TaqMan technique and were identified in 133 (40 cases and 93 controls) and 146 patients, respectively. Results:The demographic data between 2 groups are not significantly different. The genotype frequencies of PRSS1-PRSS2 (TT, TC, and CC) are 26, 13, and 1 vs. 67, 25, and 1 in cases and controls, respectively (p = 0.642). The genotype frequencies of MORC4 in female (TT, TC, and CC) are 8, 23, and 5 vs. 12, 26, and 21 in cases and controls, respectively (p = 0.071). The genotype frequencies of MORC4 in male (T and C) are 5 and 8 vs. 21 and 17 in cases and controls, respectively (p = 0.468). The allelic frequencies of MORC4 in combination of both genders (T, C) are 44 and 41 vs. 71 and 84 in cases and control, respectively (p = 0.431). In PEP cases, the allelic frequencies of PRSS1-PRSS2 (T and C) are 59 and 13 vs. 6 and 2 in mild and moderate/severe cases, respectively (p = 0.633). The allelic frequencies of MORC4 (T and C) are 38 and 39 vs. 4 and 4 in mild and moderate/severe cases, respectively (p = 0.972). Conclusion:Polymorphisms at PRSS1-PRSS2 and MORC4 are not associated with the risk or severity of post-ERCP pancreatitis.

Dataset Information

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.

Publications

Trypsin-encoding <i>PRSS1-PRSS2</i> variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report.

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