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Mechanisms of Therapy Driven Clonal Evolution in Oncogenic RAS Mutant Relapsed Acute Lymphoblastic Leukemia
dbGaP
Data Resource:  dbGaP
Point of Contact:  
Adolfo Ferrando, MD, PhD,  
Project

About This Dataset
Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL.
Core Data Elements
Number of Cases
57
Case Sex
Female (15); Male (42)
Case Age At Diagnosis
0 to 4 years (18); 5 to 9 years (25); 10 to 14 years (8); 15 to 19 years (5); Pediatric and Young Adult (<40 years) (1)
Case Race
Not Reported (57)
Case Ethnicity
Not Reported (57)
Case Disease Diagnosis
Acute Lymphoblastic Leukemia (57)
Number of Samples
179
Sample Assay Method
Whole Exome Sequencing (170); Whole Genome Sequencing (9)
Sample Anatomic Site
Peripheral Blood Lymphocytes (179)
Additional Data Elements
CLINICAL TRIAL IDENTIFIER
DBGAP STUDY IDENTIFIER
Grant Information
R01CA179044
Identification and modeling of driver genetic modules in glioblastoma
R01CA185486
(PQB5) Reconstruction of Evolutionary Networks using Cross-Sectional Genomic Data
Published In
https://doi.org/10.1073/pnas.1608420113
Charts
Male (42); Female (15)
42Male