https://scholars.lib.ntu.edu.tw/handle/123456789/537375
標題: | Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): An international study on 331 patients | 作者: | Christen F. Hoyer K. Yoshida K. HSIN-AN HOU Waldhueter N. Heuser M. Hills R.K. Chan W. Hablesreiter R. Blau O. Ochi Y. Klement P. WEN-CHIEN CHOU Blau I.-W. JIH-LUH TANG Zemojtel T. Shiraishi Y. Shiozawa Y. Thol F. Ganser A. Löwenberg B. Linch D.C. Bullinger L. Valk P.J.M. HWEI-FANG TIEN Gale R.E. Ogawa S. Damm F. |
公開日期: | 2019 | 出版社: | American Society of Hematology | 卷: | 133 | 期: | 10 | 起(迄)頁: | 1140-1151 | 來源出版物: | Blood | 摘要: | Acute myeloid leukemia with t(8;21)(q22;q22) is characterized by considerable clinical and biological heterogeneity leading to relapse in up to 40% of patients. We sequenced coding regions or hotspot areas of 66 recurrently mutated genes in a cohort of 331 t(8;21) patients. At least 1 mutation, in addition to t(8;21), was identified in 95%, with a mean of 2.2 driver mutations per patient. Recurrent mutations occurred in genes related to RAS/ RTK signaling (63.4%), epigenetic regulators (45%), cohesin complex (13.6%), MYC signaling (10.3%), and the spliceosome (7.9%). Our study identified mutations in previously unappreciated genes: GIGYF2, DHX15, and G2E3. Based on high mutant levels, pairwise precedence, and stability at relapse, epigenetic regulator mutations were likely to occur before signaling mutations. In 34% of RAS/RTKmutated patients, we identified multiple mutations in the same pathway. Deep sequencing (?42 0003) of 126 mutations in 62 complete remission samples from 56 patients identified 16 persisting mutations in 12 patients, of whom 5 lacked RUNX1-RUNX1T1 in quantitative polymerase chain reaction analysis. KIThigh mutations defined by a mutant level ?25% were associated with inferior relapse-free survival (hazard ratio, 1.96; 95% confidence interval, 1.22-3.15; P 5 .005). Together with age and white blood cell counts, JAK2, FLT3-internal tandem duplicationhigh, and KIThigh mutations were identified as significant prognostic factors for overall survival in multivariate analysis. Whole-exome sequencing was performed on 19 paired diagnosis, remission, and relapse trios. Exome-wide analysis showed an average of 16 mutations with signs of substantial clonal evolution. Based on the resemblance of diagnosis and relapse pairs, genetically stable (n 5 13) and unstable (n 5 6) subgroups could be identified. ? 2019 by The American Society of Hematology |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85062605422&doi=10.1182%2fblood-2018-05-852822&partnerID=40&md5=340055858414f5414549a3d498be8a54 https://scholars.lib.ntu.edu.tw/handle/123456789/537375 |
ISSN: | 0006-4971 | DOI: | 10.1182/blood-2018-05-852822 | SDG/關鍵字: | asxl1 protein; asxl2 protein; ccnd2 protein; CD135 antigen; cohesin; dhx15 protein; DNA methyltransferase 3A; isocitrate dehydrogenase 2; Janus kinase 2; kdm6a protein; kit protein; Myc protein; protein; protein CBFA2T1; Ras protein; rtk protein; tet2 protein; transcription factor EZH2; transcription factor RUNX1; unclassified drug; zbtb7a protein; guanosine triphosphatase; KRAS protein, human; membrane protein; NRAS protein, human; protein p21; acute myeloid leukemia; adolescent; adult; aged; allele; allogeneic hematopoietic stem cell transplantation; Article; blood; cancer prognosis; chromatin assembly and disassembly; clinical outcome; clonal evolution; cohort analysis; DNA methylation; epigenetics; female; follow up; genetic code; genomics; human; karyotyping; leukemia relapse; leukemia remission; leukemogenesis; leukocyte count; loss of function mutation; major clinical study; male; overall survival; polymerase chain reaction; priority journal; recurrence free survival; signal transduction; somatic mutation; spliceosome; whole exome sequencing; acute myeloid leukemia; chromosome 21; chromosome 8; clinical trial; dna mutational analysis; gene translocation; genetics; genomics; middle aged; multicenter study; mutation; prognosis; remission; tumor recurrence; very elderly; young adult; Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Clonal Evolution; DNA Mutational Analysis; Female; Genomics; GTP Phosphohydrolases; Humans; Leukemia, Myeloid, Acute; Male; Membrane Proteins; Middle Aged; Mutation; Neoplasm Recurrence, Local; Prognosis; Proto-Oncogene Proteins p21(ras); Remission Induction; Signal Transduction; Translocation, Genetic; Young Adult |
顯示於: | 醫學系 |
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