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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2018.1
- 수록면
- 823 - 834 (12page)
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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 twostage 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 rs2307486 was 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.
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참고문헌 (30)
참고문헌 신청
Pui CH / 2008 / Acute lymphoblastic leukaemia / Lancet 371:1030~1043
Yang JJ / 2015 / Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia / J Clin Oncol 33:1235~1242
Bhatia S / 2015 / Systemic exposure to thiopurines and risk of relapse in children with acute lymphoblastic leukemia: a children's oncology group study / JAMA Oncol 1:287~295
Cheok MH / 2006 / Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy / Nat Rev Cancer 6:117~129
Chang JG / 2002 / Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations / Pharmacogenetics 12:191~195
Yang JJ / 2015 / Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia / J Clin Oncol 33:1235~1242
Bhatia S / 2015 / Systemic exposure to thiopurines and risk of relapse in children with acute lymphoblastic leukemia: a children's oncology group study / JAMA Oncol 1:287~295
Cheok MH / 2006 / Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy / Nat Rev Cancer 6:117~129
Chang JG / 2002 / Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations / Pharmacogenetics 12:191~195
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