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 (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.

Increasing completion of asparaginase treatment in childhood acute lymphoblastic leukaemia (ALL): summary of an expert panel discussion

“…34 In addition, single-nucleotide polymorphisms (SNPs) associated with elevated risk of alcohol-associated pancreatitis including PRSS1-PRSS2 variants have also been found to impact the risk of AAP. 29 Also, a correlation between the SNPs in MYBBP1A, IL16 and SPEF2 with pancreatitis has been described. 35 Nevertheless, the impact of these variants is limited and predicting the risk of AAP and disease trajectories is not yet possible.…”

Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open–Cancer Horizons roundtable discussion

“… 5 9 10 16 18 Short-term acute complications of AAP include systemic inflammatory response syndrome (SIRS), hyperglycaemic, development of pseudocysts and pancreatic necrosis, while long-term complications include insulin-dependent diabetes and chronic pancreatitis, although the later weans off within 5–6 years after cessation of antileukaemic therapy. 31 Several studies have reported that older age and higher cumulative asparaginase dose and duration 32 correlate with higher incidences of pancreatitis, but these as well as host genome variants 33 are too weak predictors to be applied for asparaginase treatment stratification.…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“… Wolthers et al. (2017) found associations with fourteen SNPs in the theunc-51-like kinase 2 ( ULK2 ) gene (highest association with rs281366) and one SNP in G-protein signaling 6 ( RGS6 ) gene (rs17179470), nuclear factor of activated T cells 2 ( NFATC2 , rs62228256), pancreatic secretory trypsin inhibitor ( SPINK1 , rs17107315), chymotrypsin C ( CTRC , rs10436957), and Claudin-2 ( CLDN2 , rs4409525) ( Wolthers et al., 2019 ). The proteases cationic and anionic ( PRSS1-PRSS2 , rs13228878, and rs10273639) reduced the risk of pancreatitis ( Wolthers et al., 2019 ).…”