Treatment-related pancreatitis (TRP) is a serious complication occurring in children with acute lymphoblastic leukemia (ALL). Those affected are at high risk for severe organ toxicity and treatment delays that can impact outcomes. TRP is associated with asparaginase, a standard therapeutic agent in childhood ALL. Native American ancestry, older age, high-risk leukemia, and increased use of asparaginase are linked to pancreatitis risk. However, dedicated genetic studies evaluating pancreatitis in childhood ALL include few Hispanics. Thus, the genetic basis for higher risk of pancreatitis among Hispanic children with ALL remains unknown.
Cases of children with ALL treated in from 1994 through 2013 were reviewed and identified 14, all Hispanic, who developed pancreatitis related to asparaginase therapy. Forty-six controls consisting of Hispanic children treated on the same regimens without pancreatitis were selected for comparison. Total DNA isolated from whole blood was used for targeted DNA sequencing of 23 selected genes, including genes associated with pancreatitis without ALL and genes involved in asparagine metabolism.
Non-synonymous polymorphisms and frameshift deletions were detected in 15 genes. Most children with TRP had variants in ABAT, ASNS, and CFTR. Notably, children with TRP harbored many more CFTR variants (71.4%) compared with controls (39.1%). Among these, V470M (rs213950) was most frequent (OR 4.27, p = 0.025).
This is the first study of genetic factors in treatment-related pancreatitis in Hispanic children with ALL. Identifying correlative variants in ethnically vulnerable populations may improve screening to identify which patients with ALL are at greatest risk for pancreatitis.
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Yang JJ, Cheng C, Devidas M, Cao X, Fan Y, Campana D, Yang W, Neale G, Cox NJ, Scheet P, Borowitz MJ, Winick NJ, Martin PL, Willman CL, Bowman WP, Camitta BM, Carroll A, Reaman GH, Carroll WL, Loh M, Hunger SP, Pui CH, Evans WE, Relling MV (2011) Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet 43(3):237–241
Yamamoto JF, Goodman MT (2008) Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control 19(4):379–390
Kadan-Lottick NS et al (2003) Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA 290(15):2008–2014
Kearney SL, Dahlberg SE, Levy DE, Voss SD, Sallan SE, Silverman LB (2009) Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis. Pediatr Blood Cancer 53(2):162–167
Raetz EA, Salzer WL (2010) Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 32(7):554–563
Jimenez-Hernandez E et al (2015) Survival of Mexican children with acute lymphoblastic leukaemia under treatment with the protocol from the Dana-Farber Cancer Institute 00-01. Biomed Res Int 2015:576950
Gervasini G, Vagace JM (2012) Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia. Front Genet 3:249
Kawa S, Ota M, Yoshizawa K, Horiuchi A, Hamano H, Ochi Y, Nakayama K, Tokutake Y, Katsuyama Y, Saito S, Hasebe O, Kiyosawa K (2002) HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology 122(5):1264–1269
Heap GA et al (2014) HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet 46(10):1131–1134
Liu C, Yang W, Devidas M, Cheng C, Pei D, Smith C, Carroll WL, Raetz EA, Bowman WP, Larsen EC, Maloney KW, Martin PL, Mattano LA Jr, Winick NJ, Mardis ER, Fulton RS, Bhojwani D, Howard SC, Jeha S, Pui CH, Hunger SP, Evans WE, Loh ML, Relling MV (2016) Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia. J Clin Oncol 34(18):2133–2140
Audrezet MP et al (2002) Determination of the relative contribution of three genes - the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene and the pancreatic secretory trypsin inhibitor gene - to the etiology of idiopathic chronic pancreatitis. Eur J Hum Genet 10:100–106
Witt H, Luck W, Hennies HC, Claßen M, Kage A, Laß U, Landt O, Becker M (2000) Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 25:213–216
Hunger SP, Loh ML, Whitlock JA, Winick NJ, Carroll WL, Devidas M, Raetz EA, on behalf of the COG Acute Lymphoblastic Leukemia Committee (2013) Children’s Oncology Group’s 2013 blueprint for research: acute lymphoblastic leukemia. Pediatr Blood Cancer 60(6):957–963
Wang LJ, Zhang CW, Su SC, Chen HIH, Chiu YC, Lai Z, Bouamar H, Ramirez AG, Cigarroa FG, Sun LZ, Chen Y (2019) An ancestry informative marker panel design for individual ancestry estimation of Hispanic population using whole exome sequencing data. BMC Genomics 20(Suppl 12):1007
Danecek P, Auton A, Abecasis G, Albers CA, Banks E, DePristo MA, Handsaker RE, Lunter G, Marth GT, Sherry ST, McVean G, Durbin R, 1000 Genomes Project Analysis Group (2011) The variant call format and VCFtools. Bioinformatics 27(15):2156–2158
Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164
Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-Salomon R, Rubinstein W, Maglott DR (2016) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44(D1):D862–D868
Huang Y, Yang J, Ying D, Zhang Y, Shotelersuk V, Hirankarn N, Sham PC, Lau YL, Yang W (2015) HLAreporter: a tool for HLA typing from next generation sequencing data. Genome Med 7(1):25
LaRusch J, Jung J, General IJ, Lewis MD, Park HW, Brand RE, Gelrud A, Anderson MA, Banks PA, Conwell D, Lawrence C, Romagnuolo J, Baillie J, Alkaade S, Cote G, Gardner TB, Amann ST, Slivka A, Sandhu B, Aloe A, Kienholz ML, Yadav D, Barmada MM, Bahar I, Lee MG, Whitcomb DC, the North American Pancreatitis Study Group (2014) Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet 10(7):e1004376
Banerji J (2015) Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (review-hypothesis). Int J Mol Med 36(3):607–626
Chong PA et al (2013) Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability. Cold Spring Harb Perspect Med 3(3):a009522
Peng S et al (2016) Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2. Philos Trans R Soc Lond Ser B Biol Sci 371(1700):20150423
Maleth J, Hegyi P (2016) Ca2+ toxicity and mitochondrial damage in acute pancreatitis: translational overview. Philos Trans R Soc Lond Ser B Biol Sci 371(1700):20150425
Cuppens H, Lin W, Jaspers M, Costes B, Teng H, Vankeerberghen A, Jorissen M, Droogmans G, Reynaert I, Goossens M, Nilius B, Cassiman JJ (1998) Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation. J Clin Invest 101(2):487–496
Lee JH et al (2003) A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet 12(18):2321–2332
Akagi T, Yin D, Kawamata N, Bartram CR, Hofmann WK, Song JH, Miller CW, den Boer ML, Koeffler HP (2009) Functional analysis of a novel DNA polymorphism of a tandem repeated sequence in the asparagine synthetase gene in acute lymphoblastic leukemia cells. Leuk Res 33(7):991–996
Pastorczak A, Fendler W, Zalewska-Szewczyk B, Górniak P, Lejman M, Trelińska J, Walenciak J, Kowalczyk J, Szczepanski T, Mlynarski W, Polish Pediatric Leukemia/Lymphoma Study Group (2014) Asparagine synthetase (ASNS) gene polymorphism is associated with the outcome of childhood acute lymphoblastic leukemia by affecting early response to treatment. Leuk Res 38(2):180–183
Ben Tanfous M, Sharif-Askari B, Ceppi F, Laaribi H, Gagne V, Rousseau J, Labuda M, Silverman LB, Sallan SE, Neuberg D, Kutok JL, Sinnett D, Laverdiere C, Krajinovic M (2015) Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia. Clin Cancer Res 21(2):329–334
Wolthers BO et al (2017) Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. Leukemia 31(2):325–332
Wolthers BO, Frandsen TL, Patel CJ, Abaji R, Attarbaschi A, Barzilai S, Colombini A, Escherich G, Grosjean M, Krajinovic M, Larsen E, Liang DC, Möricke A, Rasmussen KK, Samarasinghe S, Silverman LB, van der Sluis I, Stanulla M, Tulstrup M, Yadav R, Yang W, Zapotocka E, Gupta R, Schmiegelow K, Ponte di Legno toxicity working group (2019) Trypsin-endoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report. Haematologica 104(3):556–563
Pant C, Deshpande A, Olyaee M, Anderson MP, Bitar A, Steele MI, Bass PF, Sferra TJ (2014) Epidemiology of acute pancreatitis in hospitalized children in the United States from 2000-2009. PLoS One 9(5):e95552
Parniczky A et al (2016) Analysis of pediatric pancreatitis (APPLE trial): pre-study protocol of a multinational prospective clinical trial. Digestion 93(2):105–110
The authors acknowledge support from St. Baldrick’s Foundation (GT), Hyundai Hope on Wheels Scholar Grant (AG), CPRIT Training Grant RP140105 (AG), CPRIT Core Facility Award RP160732 (YC), San Antonio Cancer Council Pilot Grant (AG), and May Cancer Center Support Grant 5P30CA054174.
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Grimes, A.C., Chen, Y., Bansal, H. et al. Genetic markers for treatment-related pancreatitis in a cohort of Hispanic children with acute lymphoblastic leukemia. Support Care Cancer 29, 725–731 (2021). https://doi.org/10.1007/s00520-020-05530-w
- Adverse effect
- Pediatric cancer
- Genetic variant