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Cancer Res Treat. 2018 Jul;50(3):823-834. doi: 10.4143/crt.2017.351. Epub 2017 Sep 4.

APEX1 Polymorphism and Mercaptopurine-Related Early Onset Neutropenia in Pediatric Acute Lymphoblastic Leukemia.

Kim H1,2, Seo H3,4, Park Y3,4, Min BJ3,4, Seo ME3,4, Park KD2, Shin HY2, Kim JH3,4, Kang HJ2.

Author information

1
Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
2
Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
3
Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Korea.
4
Systems Biomedical Informatics Research Center, Seoul National University, Seoul, Korea.

Abstract

Purpose:

Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients.

Materials and Methods:

Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients.

Results:

Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01).

Conclusion:

We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia.

KEYWORDS:

6-Mercaptopurine; APEX1; Acute lymphoblastic leukemia; Neutropenia; Pediatrics; NUDT15

PMID:
28882023
PMCID:
PMC6056975
DOI:
10.4143/crt.2017.351
[Indexed for MEDLINE]
Free PMC Article

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