nach oben

Erschienen in:

24.05.2020 | Original Article

Genetic markers for treatment-related pancreatitis in a cohort of Hispanic children with acute lymphoblastic leukemia

verfasst von: Allison C. Grimes, Yidong Chen, Hima Bansal, Christine Aguilar, Luz Perez Prado, Gerardo Quezada, Jaime Estrada, Gail E. Tomlinson

Erschienen in: Supportive Care in Cancer | Ausgabe 2/2021

Einloggen, um Zugang zu erhalten

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

Nur mit Berechtigung zugänglich

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):237–241CrossRef

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):379–390CrossRef

Kadan-Lottick NS et al (2003) Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA 290(15):2008–2014CrossRef

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):162–167CrossRef

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):554–563CrossRef

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 2015:576950PubMedPubMedCentral

Gervasini G, Vagace JM (2012) Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia. Front Genet 3:249CrossRef

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):1264–1269CrossRef

Heap GA et al (2014) HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet 46(10):1131–1134CrossRef

10.

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):2133–2140CrossRef

11.

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 10:100–106CrossRef

12.

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 25:213–216CrossRef

13.

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):957–963CrossRef

14.

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):1007CrossRef

15.

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):2156–2158CrossRef

16.

Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164CrossRef

17.

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–D868CrossRef

18.

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):25CrossRef

19.

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):e1004376CrossRef

20.

Banerji J (2015) Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (review-hypothesis). Int J Mol Med 36(3):607–626CrossRef

21.

Chong PA et al (2013) Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability. Cold Spring Harb Perspect Med 3(3):a009522CrossRef

22.

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

23.

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

24.

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):487–496CrossRef

25.

Lee JH et al (2003) A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet 12(18):2321–2332CrossRef

26.

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):991–996CrossRef

27.

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):180–183CrossRef

28.

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):329–334CrossRef

29.

Wolthers BO et al (2017) Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. Leukemia 31(2):325–332CrossRef

30.

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):556–563CrossRef

31.

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):e95552CrossRef

32.

Parniczky A et al (2016) Analysis of pediatric pancreatitis (APPLE trial): pre-study protocol of a multinational prospective clinical trial. Digestion 93(2):105–110CrossRef

Titel: Genetic markers for treatment-related pancreatitis in a cohort of Hispanic children with acute lymphoblastic leukemia
verfasst von: Allison C. Grimes
Yidong Chen
Hima Bansal
Christine Aguilar
Luz Perez Prado
Gerardo Quezada
Jaime Estrada
Gail E. Tomlinson
Publikationsdatum: 24.05.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Supportive Care in Cancer / Ausgabe 2/2021
Print ISSN: 0941-4355
Elektronische ISSN: 1433-7339
DOI: https://doi.org/10.1007/s00520-020-05530-w

Neu im Fachgebiet Onkologie

CAR-M-Zellen: Warten auf das große Fressen

22.05.2024 Onkologische Immuntherapie Nachrichten

Auch myeloide Immunzellen lassen sich mit chimären Antigenrezeptoren gegen Tumoren ausstatten. Solche CAR-Fresszell-Therapien werden jetzt für solide Tumoren entwickelt. Künftig soll dieser Prozess nicht mehr ex vivo, sondern per mRNA im Körper der Betroffenen erfolgen.

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Genetic markers for treatment-related pancreatitis in a cohort of Hispanic children with acute lymphoblastic leukemia