Abstract：
:Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390-400. ©2016 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Ding LW,Sun QY,Tan KT,Chien W,Mayakonda A,Yeoh AEJ,Kawamata N,Nagata Y,Xiao JF,Loh XY,Lin DC,Garg M,Jiang YY,Xu L,Lim SL,Liu LZ,Madan V,Sanada M,Fernández LT,Hema Preethi SS,Lill M,Kantarjian HM,Kornblau SM,doi
10.1158/0008-5472.CAN-16-1303subject
Has Abstractpub_date
2017-01-15 00:00:00pages
390-400issue
2eissn
0008-5472issn
1538-7445journal_volume
77pub_type
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