title: Clonality and evolutionary history of rhabdomyosarcoma.
abstract: To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. We discover several early mutations in non-RAS mutated samples and predict them to be drivers in PFN-RMS including recurrent mutation of PKN1. In contrast, we find that PAX-fusion-positive (PFP) subtype tumors have undergone whole-genome duplication in the late stage of cancer evolutionary history and have acquired fewer mutations and subclones than PFN-RMS. Moreover we predict that the PAX3-FOXO1 fusion event occurs earlier than the whole genome duplication. Our findings provide information critical to the understanding of tumorigenesis of RMS.
authors.affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Pediatric Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jack F
authors.initials: JF
authors.lastname: Shern
authors.affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jun S
authors.initials: JS
authors.lastname: Wei
authors.affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Pediatric Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Marielle E
authors.initials: ME
authors.lastname: Yohe
authors.affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Young K
authors.initials: YK
authors.lastname: Song
authors.affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Hurd
authors.affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Hongling
authors.initials: H
authors.lastname: Liao
authors.affiliation: Biospecimens Research and Tumour Bank, The Kids Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Catchpoole
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Stephen X
authors.initials: SX
authors.lastname: Skapek
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Frederic G
authors.initials: FG
authors.lastname: Barr
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Hawkins
authors.affiliation: Genetics Branch, Oncogenomics Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Pediatric Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D019656:Loss of Heterozygosity; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051761:Paired Box Transcription Factors / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D015514:Oncogene Proteins, Fusion; C471563:PAX3-FOXO1A fusion protein, human; D051761:Paired Box Transcription Factors