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. 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)

Ke-Wei Zhu  1   2 , Peng Chen  1   2 , Dao-Yu Zhang  1   2 , Han Yan  1   2 , Han Liu  1   2 , Li-Na Cen  1   2 , Yan-Ling Liu  1   2 , Shan Cao  1   2 , Gan Zhou  1   2 , Hui Zeng  3 , Shu-Ping Chen  3 , Xie-Lan Zhao  3 , Xiao-Ping Chen  4   5   6   7
Affiliations

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

Ke-Wei Zhu et al. J Transl Med. .

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).

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Figures

Fig. 1
Fig. 1
Schematic diagram of the Ara-C metabolizing pathway
Fig. 2
Fig. 2
eQTL analysis of 8 candidate SNPs selected in the study. a NME1 rs3760468; b NME1 rs2302254; c NME1–NME2 rs3744660; d SAMHD1 rs6029941; e SAMHD1 rs6102991; f RRM1 rs2412344; g RRM1 rs183484; h RRM2 rs1130609
Fig. 3
Fig. 3
Comparison of relapse-free survival (RFS) in AML patients among/between genotypes of NME1 rs3760468 (a); NME1 rs2302254 (b); NME2 rs3744660 (c); and RRM2 rs1130609 (d)
Fig. 4
Fig. 4
Comparison of overall survival (OS) in AML patients among/between genotypes of NME1 rs3760468 (a); NME2 rs3744660 (b); RRM1 rs183484 (c); and RRM2 rs1130609 (d)
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