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PLoS Genet. 2014 Jul 10;10(7):e1004475. doi: 10.1371/journal.pgen.1004475. eCollection 2014 Jul.

The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation.

Author information

1
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.
2
Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
3
Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
4
The Tumour Bank, The Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
5
Department of Pathology, University of Valencia, Valencia, Spain.
6
Center for Personalized Medicine, Children's Hospital Los Angeles, University of Southern California Los Angeles, Los Angeles, California, United States of America.
7
Laboratory of Experimental Oncology, Rizzoli Institute, Bologna, Italy.
8
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
9
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia, United States of America.

Erratum in

  • PLoS Genet. 2014 Aug;10(8):e1004629.

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.

PMID:
25010205
PMCID:
PMC4091782
DOI:
10.1371/journal.pgen.1004475
[Indexed for MEDLINE]
Free PMC Article

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