title: The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation.
abstract: The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Brohl
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Solomon
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Chang
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Young
authors.initials: Y
authors.lastname: Song
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sivasish
authors.initials: S
authors.lastname: Sindiri
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Patidar
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, 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: Oncogenomics Section, Pediatric Oncology Branch, 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: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jack F
authors.initials: JF
authors.lastname: Shern
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, 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: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wen
authors.affiliation: The Tumour Bank, The Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: Julia
authors.initials: J
authors.lastname: Gerard
authors.affiliation: The Tumour Bank, The Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: Jung-Sik
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Valencia, Valencia, Spain.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Lopez Guerrero
authors.affiliation: Department of Pathology, University of Valencia, Valencia, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Machado
authors.affiliation: Center for Personalized Medicine, Children's Hospital Los Angeles, University of Southern California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wai
authors.affiliation: Laboratory of Experimental Oncology, Rizzoli Institute, Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.affiliation: Center for Personalized Medicine, Children's Hospital Los Angeles, University of Southern California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Triche
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Horvai
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, 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: The Tumour Bank, The Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Catchpool
authors.affiliation: Department of Pathology, University of Valencia, Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Llombart-Bosch
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia, United States of America.
authors.forename: Todd
authors.initials: T
authors.lastname: Waldman
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
mesh_terms: D000293:Adolescent; D000328:Adult; D034961:Antigens, Nuclear / Q000235:genetics*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D017353:Gene Deletion; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; C508565:STAG2 protein, human; D000097722:Cohesins