Allison C Grimes1,2, Yidong Chen2,3, Hima Bansal2, Christine Aguilar1,2, Luz Perez Prado2, Gerardo Quezada4,5, Jaime Estrada4, Gail E Tomlinson6,7. 1. Department of Pediatrics, University of Texas Health Science Center San Antonio, San Antonio, TX, USA. 2. Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, TX, USA. 3. Department of Population Health Sciences, University of Texas Health Science Center San Antonio, San Antonio, TX, USA. 4. Methodist Children's Hospital, San Antonio, TX, USA. 5. Children's Hospital of San Antonio, San Antonio, TX, USA. 6. Department of Pediatrics, University of Texas Health Science Center San Antonio, San Antonio, TX, USA. tomlinsong@uthscsa.edu. 7. Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, TX, USA. tomlinsong@uthscsa.edu.
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.
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.
Entities:
Keywords:
Adverse effect; Genetic variant; Leukemia; Pancreatitis; Pediatric cancer
Authors: Elva Jiménez-Hernández; Ethel Zulie Jaimes-Reyes; José Arellano-Galindo; Xochiketzalli García-Jiménez; Héctor Manuel Tiznado-García; María Teresa Dueñas-González; Octavio Martínez Villegas; Berenice Sánchez-Jara; Vilma Carolina Bekker-Méndez; María Guadalupe Ortíz-Torres; Antonio Ortíz-Fernández; Teresa Marín-Palomares; Juan Manuel Mejía-Aranguré Journal: Biomed Res Int Date: 2015-03-26 Impact factor: 3.411