GSTT1 copy number gain is a poor predictive marker for escalated-dose imatinib treatment in chronic myeloid leukemia: genetic predictive marker found using array comparative genomic hybridization |
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| Authors: | Koh Youngil Kim Dae-Young Park Sung-Hyo Jung Seung-Hyun Park Eunkyung Kim Hyeoung-Joon Sohn Sang Kyun Joo Young Don Kim Seok Jin Shin Ho-Jin Kim Sung-Hyun Song Hong Suk Chung Jooseop Kim Inho Yoon Sung-Soo Kim Byoung Kook Shin Seung-Hun Chung Yeun-Jun Park Seonyang |
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| Affiliation: | aDepartment of Internal Medicine, Seoul National University Hospital, Seoul National University, 101 Daehagro, Jongno-Ku, Seoul 110-744, Korea;bDepartment of Internal Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea;cCML Working Party, Korean Society of Hematology, Seoul, Korea;dDiagnostic DNA chip center, Seoul National University College of Medicine, Seoul, Korea;eDepartment of Microbiology, Integrated Research Center for Genome Polymorphism, Catholic University Medical College, Seocho-Ku, Seoul 137-701, Korea;fDepartment of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea;gDepartment of Internal Medicine, Chonnam National University Hospital, Chonnam National University, Gwangju, Korea;hDepartment of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu, Korea;iDepartment of Internal Medicine, Pusan Paik Hospital, Inje University, Busan, Korea;jDepartment of Internal Medicine, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea;kDepartment of Internal Medicine, Pusan National University Hospital, Pusan National University, Busan, Korea;lDepartment of Internal Medicine, Dong-A university hospital, Busan, Korea;mDepartment of Internal Medicine, Keimyung University, Dongsan Medical Center, Daegu, Korea |
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| Abstract: | In a study population of 45 patients who were previously enrolled in an imatinib dose escalation trial, genome-wide screening for regions of genetic gains and losses was performed using array comparative genomic hybridization (aCGH). Early molecular response (EMR), defined as >50% reduction in the ratio of BCR-ABL1 to ABL1 within 6 months after dose escalation, was a major endpoint for analysis. After aCGH analysis, copy number change of four genes was investigated in 52 patients as a validation. Copy number gain in 16p11.2 was more frequently observed in patients with EMR than in patients who failed to achieve EMR (P = 0.034). A tendency for increased copy number in 22q11.23 in patients without EMR and for decreased copy number in 17q12 in patients with EMR was observed (P = 0.072 and P = 0.070, respectively). For GSTT1, in 22q11.23, copy number gain was observed in patients without EMR (P = 0.035). GSTT1 copy number gain was related to short time to treatment failure (TTFx) in patients without BCR–ABL1 mutations (P = 0.007). In multivariate analysis, GSTT1 copy number gain was an independent predictive factor for short TTFx (P = 0.020). We conclude that chromosome regions 16p11.2, 22q11.23, and 17q12 are potential locations related to response in imatinib dose escalation therapy for CML. GSTT1 copy number gain is a genetic change affecting outcome in this setting. |
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