Subclonal mutations in SETBP1 confer a poor prognosis in juvenile myelomonocytic leukemia.
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood associated with a poor prognosis. Recently, massively parallel sequencing has identified recurrent mutations in the SKI domain of SETBP1 in a variety of myeloid disorders. These lesions were detected in nearly 10% of patients with JMML and have been characterized as secondary events. We hypothesized that rare subclones with SETBP1 mutations are present at diagnosis in a large portion of patients who relapse, but are below the limits of detection for conventional deep sequencing platforms. Using droplet digital polymerase chain reaction, we identified SETBP1 mutations in 17/56 (30%) of patients who were treated in the Children's Oncology Group sponsored clinical trial, AAML0122. Five-year event-free survival in patients with SETBP1 mutations was 18% ± 9% compared with 51% ± 8% for those without mutations (P = .006).
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA;
Elliot
http://orcid.org/0000-0001-7032-4623
E
Stieglitz
Bio-Rad Laboratories, Hercules, CA;
Camille B
CB
Troup
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA;
Laura C
LC
Gelston
Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA;
John
J
Haliburton
Center for Advanced Technology, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA;
Eric D
ED
Chow
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA;
Kristie B
KB
Yu
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA;
Jon
J
Akutagawa
Broad Institute, Cambridge, MA;
Amaro N
AN
Taylor-Weiner
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR;
Y Lucy
YL
Liu
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN;
Yong-Dong
YD
Wang
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA;
Kyle
K
Beckman
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR;
Peter D
PD
Emanuel
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA;
Benjamin S
BS
Braun
Department of Bioengineering and Therapeutic Sciences, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA;
Adam
A
Abate
Children's Oncology Group, Monrovia, CA;
Robert B
RB
Gerbing
Keck School of Medicine, University of Southern California, Los Angeles, CA; and.
Todd A
http://orcid.org/0000-0002-6772-6581
TA
Alonzo
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.
Mignon L
ML
Loh
D002352:Carrier Proteins / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate
D002352:Carrier Proteins; D009687:Nuclear Proteins; C425066:SETBP1 protein, human