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

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.

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Data availability

The authors are in complete control of the data described in the manuscript. All data obtained in this work is uploaded as Supplementary Tables (Online Resources).

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Funding

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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Correspondence to Gail E. Tomlinson.

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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

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Keywords

  • Pancreatitis
  • Adverse effect
  • Pediatric cancer
  • Genetic variant
  • Leukemia