Genetic mutational profiling analysis of T cell acute lymphoblastic leukemia reveal mutant FBXW7 as a prognostic indicator for inferior survival.
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.
Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.|Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Lan
L
Yuan
Departments of Rheumatology and Occupational Medicine and Hematology, Huashan Hospital of Fudan University, Shanghai, China.
Ling
L
Lu
Children's Hospital of Shanghai Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yongchen
Y
Yang
Children's Hospital of Shanghai Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Hengjuan
H
Sun
Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.|Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Xi
X
Chen
Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.|Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Yi
Y
Huang
Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.|Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Xingjuan
X
Wang
Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China.|Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China.|Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Lin
L
Zou
Center for Clinical Molecular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China. Liming.Bao@Dartmouth.edu.|Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. Liming.Bao@Dartmouth.edu.|Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, China. Liming.Bao@Dartmouth.edu.|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.|Department of Pathology and Laboratory Medicine, Geisel School of Medicine Dartmouth College, One Medical Center Drive, Lebanon, NH, 03756, USA. Liming.Bao@Dartmouth.edu.
Liming
L
Bao
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044767:Ubiquitin-Protein Ligases
FBXW7; Mutations; NOTCH1; Prognosis; T cell acute lymphoblastic leukemia