title: 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.
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.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University, 101 Daehagro, Jongno-Ku, Seoul 110-744, Korea.
authors.forename: Youngil
authors.initials: Y
authors.lastname: Koh
authors.forename: Dae-Young
authors.initials: DY
authors.lastname: Kim
authors.forename: Sung-Hyo
authors.initials: SH
authors.lastname: Park
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Jung
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Park
authors.forename: Hyeoung-Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sang Kyun
authors.initials: SK
authors.lastname: Sohn
authors.forename: Young Don
authors.initials: YD
authors.lastname: Joo
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Shin
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Hong Suk
authors.initials: HS
authors.lastname: Song
authors.forename: Jooseop
authors.initials: J
authors.lastname: Chung
authors.forename: Inho
authors.initials: I
authors.lastname: Kim
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
authors.forename: Byoung Kook
authors.initials: BK
authors.lastname: Kim
authors.forename: Seung-Hun
authors.initials: SH
authors.lastname: Shin
authors.forename: Yeun-Jun
authors.initials: YJ
authors.lastname: Chung
authors.forename: Seonyang
authors.initials: S
authors.lastname: Park
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D014408:Biomarkers, Tumor; D055028:Comparative Genomic Hybridization; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic; D005819:Genetic Markers; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D011237:Predictive Value of Tests; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D005819:Genetic Markers; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D016044:Fusion Proteins, bcr-abl