The IFNG (IFN-gamma) genotype predicts cytogenetic and molecular response to imatinib therapy in chronic myeloid leukemia.
OBJECTIVE
The present study analyzed treatment outcomes of imatinib therapy by interindividual genetic variants in candidate biological pathways of chronic myeloid leukemia (CML) such as apoptosis, angiogenesis, IFN-γ signaling pathways, or drug transport/metabolism of imatinib.


METHODS
Peripheral blood DNAs were genotyped for 79 single nucleotide polymorphism markers involved in the pathways of apoptosis, angiogenesis, myeloid cell growth, xenobiotic metabolism, WT1 signaling, IFN signaling, and others in CML patients who were included in discovery (n = 229, Canada) and validation cohorts (n = 187, Korea).


RESULTS
We found several genotypes associated with complete cytogenetic response: IFNG (rs1861494, rs2069705), FASL (rs763110), FAS (rs2234767, rs2234978), VEGFR2 (rs1531289), and WT1 (rs2234590); with major molecular response: IFNG (rs1861494, rs2069705), BIRC5 (rs9904341), FAS (rs2234978), and ABCG2 (rs2231142); with loss of response: IFNG (rs2069705), IFNGR2 (rs9808753), BIRC5 (rs9904341), and ORM (rs3182041); and with treatment failure: IFNG (rs2069705), JAK3 (rs3212713), and ORM (rs3182041). External validation for the above significant genotypes confirmed that the IFNG genotype (rs2069705) was predictive of complete cytogenetic response (hazard ratio, 2.17; P < 0.001) and major molecular response (hazard ratio, 1.96; P = 0.0001) in validation cohorts of Korean ethnicity.


CONCLUSIONS
The IFNG genotype was predictive for response to imatinib therapy, suggesting potential involvement of the IFN-γ signaling pathway in the mechanism of action of imatinib in CML.
Chronic Myelogenous Leukemia Group, Department of Hematology/Medical Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. drkiim@medimail.co.kr
Dong Hwan Dennis
DH
Kim
Jee Hyun
JH
Kong
Ji Young
JY
Byeun
Chul Won
CW
Jung
Wei
W
Xu
Xiangdong
X
Liu
Suzanne
S
Kamel-Reid
Yeo-Keyoung
YK
Kim
Hyeoung-Joon
HJ
Kim
Jeffrey H
JH
Lipton
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D020732:Cytogenetic Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D010879:Piperazines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011743:Pyrimidines / Q000627:therapeutic use*; D055815:Young Adult
D000970:Antineoplastic Agents; D001549:Benzamides; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D010879:Piperazines; D011743:Pyrimidines; D007371:Interferon-gamma; D000068877:Imatinib Mesylate