Cancer Res Treat.  2018 Jul;50(3):823-834. 10.4143/crt.2017.351.

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

• Kim H
• Seo H
• Park Y
• Min BJ
• Seo ME
• Park KD
• Shin HY
• Kim JH
• Kang HJ

• KMID: 2417871
• DOI: http://doi.org/10.4143/crt.2017.351

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.

Keyword

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

MeSH Terms

6-Mercaptopurine
Alleles
Computational Biology
Cytochrome P-450 CYP1A1
Cytoprotection
DNA Damage
Genotype
Humans
Incidence
Neutropenia*
Pediatrics
Precursor Cell Lymphoblastic Leukemia-Lymphoma*
6-Mercaptopurine
Cytochrome P-450 CYP1A1

Figure

• 

  Fig. 1. Primary targeted sequencing data analysis steps. SIFT, scale-invariant feature transform; CADD, combined annotation dependent depletion; PP2, PolyPhen2; NP30, 30 patients with neutropenia; CTRL6, 6 patients without neutropenia; EAS490, 490 East Asian data.

• 

  Fig. 2. Estimated cumulative incidence of mercaptopurine-related neutropenia according to the ABCC4 rs3765534 (A), APEX1 rs2307486 (B), and NUDT15 rs116855232 (C) genotypes. ANC, absolute neutrophil count.

• 

  Fig. 3. Average doses of mercaptopurine (MP) (A) and methotrexate (MTX) (B) administered during the second and last maintenance cycles according to the NUDT15 rs116855232 genotype.

Reference

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