期刊
CANCER MEDICINE
卷 10, 期 14, 页码 4864-4873出版社
WILEY
DOI: 10.1002/cam4.4024
关键词
clonal selection; genomics; relapse; T-ALL; teenagers and young adults
类别
资金
- Kay Kendall Leukaemia Fund [KKLF417]
- Leukaemia & Lymphoma Research
- European Hematology Association-EHA Partner Fellowship [2011/01]
- Lady Tata Memorial Trust-LTMT International Award for Research in Leukaemia
- Ministry of Health, INCA-Brazil
- Bloodwise
- INCA
- CNPq [301594/2015-5, 310877/2019-5]
- FAPERJ [E-26/110.712/2012, E-26/202.577/2019]
- Fundacao do Cancer, SwissBridge Fund
- Hungarian National Research, Development and Innovation Office-NKFIH [119950, 134253]
- New National Excellence Program of the Ministry for Innovation and Technology [UNKP-20-5-SE-22]
- Hungarian Academy of Sciences [BO/00320/18/5]
- EU's Horizon 2020 Research and Innovation Program [739593]
- Institute of Cancer Research
- Wellcome Trust [105104/Z/14/Z]
- Wellcome Trust [105104/Z/14/Z] Funding Source: researchfish
The study found that adolescent and young adult T-ALL does not have specific genetic abnormalities compared to pediatric or adult T-ALL, showing a transitional genomic profile.
Background: Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T-cell acute lymphoblastic leukemia (T-ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T-ALL has a specific biological-molecular profile distinct from pediatric or adult T-ALL. Methods: Genomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15-26 years with primary or relapsed T-ALL, using a combination of Genome-Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real-time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1-14 years), 439 TYA (15-24 years) and 381 adult (>= 25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search. Results: Genomic characterization of this large cohort of TYA T-ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation - relapsed T-ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways. Conclusions: All genetic aberrations in TYA T-ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T-ALL exhibits a transitional genomic profile. Analysis of matched presentation - relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub-clones associated with drug resistance (NT5C2 and TP53 mutations) and re-iterative mutation of known key T-ALL drivers, including NOTCH1.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据