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

Abstract

PurposeMercaptopurine (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 MethodsTargeted 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.ResultsUsing 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).ConclusionWe 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.

NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia

“…A previous study reported that East Asian genetic ancestry remained associated with 6-MP dose intensity after adjusting for rs116855232 [ 17 ], suggesting that there may be other undiscovered genetic or environmental factors affecting Asians. Kim et al [ 32 ], recently reported that APEX1 rs2307486 variants conferred an increased risk of mercaptopurine-related early onset neutropenia in Korean pediatric ALL patients.…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“…Genetic variants in Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) have been studied in relation to a more general sensitivity to antimetabolite active drugs, as human APEX1 is involved in DNA base excision repair pathway. In Asian populations APEX1 (rs2307486) variant resulted in an increased risk of 6MP-related early onset neutropenia (Kim et al, 2018).…”

“…Transporter genes have also been studied and variants in the ABCB1 gene (C1236T) have found to be associated with increased sensitivity to 6MP (Gervasini et al, 2017), as well as variant genes in efflux transporter ABCC4 (Kim et al, 2018;Tanaka et al, 2018). These findings have been reported in small studies and need confirmation before being introduced in clinical practice.…”

Homozygote CRIM1 variant is associated with thiopurine-induced neutropenia in leukemic patients with both wildtype NUDT15 and TPMT

“…The recorded 6-MP dose per square meter of the body surface over a 12-week cycle was used to define the actual administered dose as a percentage of the planned dose as the last-cycle DIP. Since East Asian ancestry requires significantly lower 6-MP dose intensity compared to the other ethnic groups [5], patients who require less than 25% of the protocol planned dose were classified as MP-intolerant groups [6]. We have previously presented a detailed description of the subjects and a summary of the measurements [7].…”

“…5 Seoul National University Cancer Research Institute, Seoul, South Korea. 6 Department of Pediatrics, Seoul National University Bundang Hospital, Seoul, South Korea. 7 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.…”