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J Transl Med. 2018 Apr 10;16(1):90. doi: 10.1186/s12967-018-1463-1.

Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML).

Zhu KW1,2, Chen P1,2, Zhang DY1,2, Yan H1,2, Liu H1,2, Cen LN1,2, Liu YL1,2, Cao S1,2, Zhou G1,2, Zeng H3, Chen SP3, Zhao XL3, Chen XP4,5,6,7.

Author information

1
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410078, People's Republic of China.
2
Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, People's Republic of China.
3
Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410078, People's Republic of China.
4
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410078, People's Republic of China. chenxp74@hotmail.com.
5
Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, People's Republic of China. chenxp74@hotmail.com.
6
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China. chenxp74@hotmail.com.
7
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. chenxp74@hotmail.com.

Abstract

BACKGROUND:

Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP.

METHODS:

A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed.

RESULTS:

Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients.

CONCLUSION:

Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

KEYWORDS:

Adult acute myeloid leukaemia (AML); Cytarabine arabinoside (Ara-C); Single nucleotide polymorphisms (SNPs)

PMID:
29631596
PMCID:
PMC5892020
DOI:
10.1186/s12967-018-1463-1
[Indexed for MEDLINE]
Free PMC Article

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