title: Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse.
abstract: The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. Cancer Res; 76(8); 2197-205. ©2016 AACR.
authors.affiliation: Arkansas Children's Hospital Research Institute and the University of Arkansas for Medical Sciences, Little Rock, Arkansas. Children's Oncology Group, Monrovia, California.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Farrar
authors.affiliation: Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Schuback
authors.affiliation: Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington.
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Ries
authors.affiliation: Ron Matricaria Institute of Molecular Medicine, Phoenix Children's Hospital and the University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wai
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Hampton
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. Doctors Hospital at Renaissance, Edinburg, Texas.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Trevino
authors.affiliation: Children's Oncology Group, Monrovia, California. University of Southern California, Los Angeles, California.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.affiliation: Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Guidry Auvil
authors.affiliation: Center for Bioinformatics and Information Technology, National Cancer Institute, Rockville, Maryland.
authors.forename: Tanja M
authors.initials: TM
authors.lastname: Davidsen
authors.affiliation: Center for Bioinformatics and Information Technology, National Cancer Institute, Rockville, Maryland.
authors.forename: Patee
authors.initials: P
authors.lastname: Gesuwan
authors.affiliation: Center for Bioinformatics and Information Technology, National Cancer Institute, Rockville, Maryland.
authors.forename: Leandro
authors.initials: L
authors.lastname: Hermida
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Ninad
authors.initials: N
authors.lastname: Dewal
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Navin
authors.initials: N
authors.lastname: Rustagi
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Lora R
authors.initials: LR
authors.lastname: Lewis
authors.affiliation: Children's Mercy Hospitals and Clinics, Kansas City, Missouri.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Gamis
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.affiliation: Children's Oncology Group, Monrovia, California. Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington. smeshinc@fredhutch.org.
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D012008:Recurrence