Single nucleotide polymorphisms in apoptosis pathway are associated with response to imatinib therapy in chronic myeloid leukemia

Qiaoli Zheng; Jiang Cao; Nada Hamad; Hyeoung-Joon Kim; Joon Ho Moon; Sang Kyun Sohn; Chul Won Jung; Jeffrey H Lipton; Dennis Dong Hwan Kim

doi:10.1186/s12967-016-0837-5

Single nucleotide polymorphisms in apoptosis pathway are associated with response to imatinib therapy in chronic myeloid leukemia

J Transl Med. 2016 Mar 24:14:82. doi: 10.1186/s12967-016-0837-5.

Authors

Qiaoli Zheng^{1

2}, Jiang Cao³, Nada Hamad^{4

5}, Hyeoung-Joon Kim⁶, Joon Ho Moon⁷, Sang Kyun Sohn⁷, Chul Won Jung⁸, Jeffrey H Lipton^{4

5}, Dennis Dong Hwan Kim^{4

5}

Affiliations

¹ Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
² Clinical Research Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China.
³ Clinical Research Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China. caoj@zju.edu.cn.
⁴ Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.
⁵ Department of Medicine, University of Toronto, Toronto, Canada.
⁶ Department of Hematology/Oncology, Chonnam National University Hwasun Hospital, Chonnam National University, Hwasun, South Korea.
⁷ Department of Hematology/Oncology, Kyungpook National University Hospital, Kyungpook National University, Daegu, South Korea.
⁸ Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. leukemia1@skku.edu.

Abstract

Background: The mechanism of action of imatinib is known to involve the Fas-mediated apoptosis pathway. Consequently inter-individual variations in this apoptosis pathway might be associated with imatinib response or resistance.

Methods: This study attempted to focus on eight genotypes in the apoptosis pathway including FAS (rs1800682, rs2229521, rs2234767 and rs2234978), FASLG (rs763110), CASP10 (rs13006529), and APAF1 (rs1439123, rs2288713) and analyzed their association with treatment outcomes including molecular response with 4.5 log reduction (MR4.5), following imatinib therapy in 187 Korean CML patients.

Results: The GG/GA genotype in FAS (rs2234767) showed a higher rate of MR4.5 than the AA genotype (at 5 years 59.7 vs 37.4 %, p = 0.013). Using a bootstrap procedure for internal validation we confirmed that FAS (rs2234767) correlates with MR4.5 (p = 0.050). Multivariate analysis confirmed that the FAS genotype (rs2234767) is an independent surrogate for MR4.5 (p = 0.019, HR 0.43, 95 % CI [0.22-0.87]).

Conclusions: The Fas/FasL signaling pathway may represent the major pathway that mediates apoptosis in CML treated with imatinib. SNP markers in the apoptosis pathway including FAS genotype (rs2234767) can be potential surrogates for predicting deeper molecular response after imatinib therapy.

Keywords: Apoptosis pathway; Chronic myeloid leukemia; Imatinib; Single nucleotide polymorphisms.

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Apoptosis / genetics*
Child
Demography
Female
Genotype
Humans
Imatinib Mesylate / pharmacology
Imatinib Mesylate / therapeutic use*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
Male
Middle Aged
Multivariate Analysis
Polymorphism, Single Nucleotide / genetics*
Prognosis
Reproducibility of Results
Signal Transduction / genetics*
Treatment Outcome
Young Adult

Substances

Imatinib Mesylate