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Ann Hematol. 2015 Nov;94(11):1817-28. doi: 10.1007/s00277-015-2474-0. Epub 2015 Sep 5.

Genetic mutational profiling analysis of T cell acute lymphoblastic leukemia reveal mutant FBXW7 as a prognostic indicator for inferior survival.

Yuan L1,2,3,4, Lu L5, Yang Y6, Sun H6, Chen X1,2,3,4, Huang Y1,2,3,4, Wang X1,2,3,4, Zou L1,2,3,4, Bao L7,8,9,10,11.

Author information

1
Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.
2
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
3
Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China.
4
Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
5
Departments of Rheumatology and Occupational Medicine and Hematology, Huashan Hospital of Fudan University, Shanghai, China.
6
Children's Hospital of Shanghai Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
7
Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China. Liming.Bao@Dartmouth.edu.
8
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. Liming.Bao@Dartmouth.edu.
9
Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China. Liming.Bao@Dartmouth.edu.
10
Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. Liming.Bao@Dartmouth.edu.
11
Department of Pathology and Laboratory Medicine, Geisel School of Medicine Dartmouth College, One Medical Center Drive, Lebanon, NH, 03756, USA. Liming.Bao@Dartmouth.edu.

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplasm for which there are currently no adequate biomarkers for developing risk-adapted therapeutic regimens to improve the treatment outcome. In this prospective study of 83 Chinese patients (54 children and 29 adults) with de novo T-ALL, we analyzed mutations in 11 T-ALL genes: NOTCH1, FBXW7, PHF6, PTEN, N-RAS, K-RAS, WT1, IL7R, PIK3CA, PIK3RA, and AKT1. NOTCH1 mutations were identified in 51.9 and 37.9 % of pediatric and adult patients, respectively, and these patients showed improved overall survival (OS) and event-free survival (EFS). The FBXW7 mutant was present in 25.9 and 6.9 % of pediatric and adult patients, respectively, and was associated with inferior OS and EFS in pediatric T-ALL. Multivariate analysis revealed that mutant FBXW7 was an independent prognostic indicator for inferior EFS (hazard ratio [HR] 4.38; 95 % confidence interval [CI] 1.15-16.71; p = 0.03) and tended to be associated with reduced OS (HR 2.81; 95 % CI 0.91-8.69; p = 0.074) in pediatric T-ALL. Mutant PHF6 was present in 13 and 20.7 % of our childhood and adult cohorts, respectively, while PTEN mutations were noted in 11.1 % of the pediatric patients. PTEN and NOTCH1 mutations were almost mutually exclusive, while IL7R and WT1 mutations were rare in pediatric T-ALL and PTPN11 and AKT1 mutations were infrequent in adult T-ALL. This study revealed differences in the mutational profiles of pediatric and adult T-ALL and suggests mutant FBXW7 as an independent prognostic indicator for inferior survival in pediatric T-ALL.

KEYWORDS:

FBXW7; Mutations; NOTCH1; Prognosis; T cell acute lymphoblastic leukemia

PMID:
26341754
DOI:
10.1007/s00277-015-2474-0
[Indexed for MEDLINE]

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