Genetic markers for treatment-related pancreatitis in a cohort of Hispanic children with acute lymphoblastic leukemia
- 24 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Supportive Care in Cancer
- Vol. 29 (2), 725-731
- https://doi.org/10.1007/s00520-020-05530-w
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.Funding Information
- NIH (5P30CA054174-21)
- St. Baldricks Foundation (N/A)
- Hyundai Hope On Wheels (N/A)
- UT Health Mays Cancer Center (N/A)
- Cancer Prevention and Research Institute of Texas (RP101491, RP160732)
This publication has 32 references indexed in Scilit:
- Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemiaFrontiers in Genetics, 2012
- The variant call format and VCFtoolsBioinformatics, 2011
- Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemiaNature Genetics, 2011
- Tolerability and Efficacy of L-Asparaginase Therapy in Pediatric Patients With Acute Lymphoblastic LeukemiaJournal of Pediatric Hematology/Oncology, 2010
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Functional analysis of a novel DNA polymorphism of a tandem repeated sequence in the asparagine synthetase gene in acute lymphoblastic leukemia cellsLeukemia Research, 2009
- Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase‐associated pancreatitisPediatric Blood & Cancer, 2009
- A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseasesHuman Molecular Genetics, 2003
- 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 pancreatitisEuropean Journal of Human Genetics, 2002
- 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.JCI Insight, 1998