Correction: The Genomic Landscape of the Ewing Sarcoma Family of Tumors Reveals Recurrent STAG2 Mutation

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. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability: All data underlying the findings are fully available for general research use to applicants whose data access request is approved by the dbGaP Data Access Committee (dbGaP accession number phs000768.v1.p1). Because of confidentiality issues associated with human subject data, they cannot be made available without restriction.

[1]  Jun S. Wei,et al.  The Genomic Landscape of the Ewing Sarcoma Family of Tumors Reveals Recurrent STAG2 Mutation , 2014, PLoS genetics.

[2]  M. Nikiforova,et al.  ETV6‐NTRK3 is a common chromosomal rearrangement in radiation‐associated thyroid cancer , 2014, Cancer.

[3]  G. Getz,et al.  Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. , 2014, Cancer discovery.

[4]  Heather L. Mulder,et al.  Targeting oxidative stress in embryonal rhabdomyosarcoma. , 2013, Cancer cell.

[5]  M. Rubin,et al.  Frequent truncating mutations of STAG2 in bladder cancer , 2013, Nature Genetics.

[6]  A. Valencia,et al.  Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy , 2013, Nature Genetics.

[7]  N. Yoo,et al.  Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability. , 2013, Human pathology.

[8]  Benjamin J. Raphael,et al.  Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. , 2013, The New England journal of medicine.

[9]  E Mardis,et al.  Clonal diversity of recurrently mutated genes in myelodysplastic syndromes , 2013, Leukemia.

[10]  R. Siebert,et al.  High‐resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors , 2013, Genes, chromosomes & cancer.

[11]  Masao Nagasaki,et al.  Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms , 2012, Nature Genetics.

[12]  Kristian Cibulskis,et al.  A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. , 2012, The Journal of clinical investigation.

[13]  D. Pisano,et al.  The specific contributions of cohesin-SA1 to cohesion and gene expression , 2012, Cell cycle.

[14]  S. Ramaswamy,et al.  Systematic identification of genomic markers of drug sensitivity in cancer cells , 2012, Nature.

[15]  C. Antonescu,et al.  High prevalence of CIC fusion with double‐homeobox (DUX4) transcription factors in EWSR1‐negative undifferentiated small blue round cell sarcomas , 2012, Genes, chromosomes & cancer.

[16]  P. Hieter,et al.  Synthetic Lethality of Cohesins with PARPs and Replication Fork Mediators , 2012, PLoS genetics.

[17]  D. Zwijnenburg,et al.  Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes , 2012, Nature.

[18]  Matthew W. Wilson,et al.  A Novel Retinoblastoma Therapy from Genomic and Epigenetic Analyses , 2011, Nature.

[19]  Hongtao Yu,et al.  Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer , 2011, Science.

[20]  S. Salzberg,et al.  TopHat-Fusion: an algorithm for discovery of novel fusion transcripts , 2011, Genome Biology.

[21]  S. Lessnick,et al.  Promiscuous partnerships in Ewing's sarcoma. , 2011, Cancer genetics.

[22]  Süleyman Cenk Sahinalp,et al.  deFuse: An Algorithm for Gene Fusion Discovery in Tumor RNA-Seq Data , 2011, PLoS Comput. Biol..

[23]  A. Llombart‐Bosch,et al.  Clinicopathological significance of cell cycle regulation markers in a large series of genetically confirmed Ewing's Sarcoma Family of Tumors , 2011, International journal of cancer.

[24]  Jonathan W. Pillow,et al.  POSTER PRESENTATION Open Access , 2013 .

[25]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[26]  Cole Trapnell,et al.  Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. , 2010, Nature biotechnology.

[27]  B. Perez-Ordonez,et al.  Mammary Analogue Secretory Carcinoma of Salivary Glands, Containing the ETV6-NTRK3 Fusion Gene: A Hitherto Undescribed Salivary Gland Tumor Entity , 2010, The American journal of surgical pathology.

[28]  Robert B. Hartlage,et al.  This PDF file includes: Materials and Methods , 2009 .

[29]  K. Rothkamm,et al.  Cohesin promotes the repair of ionizing radiation-induced DNA double-strand breaks in replicated chromatin , 2009, Nucleic acids research.

[30]  Steven J. M. Jones,et al.  Circos: an information aesthetic for comparative genomics. , 2009, Genome research.

[31]  H. Tanke,et al.  The NFATc2 Gene Is Involved in a Novel Cloned Translocation in a Ewing Sarcoma Variant That Couples Its Function in Immunology to Oncology , 2009, Clinical Cancer Research.

[32]  Samuel Kaski,et al.  Combined use of expression and CGH arrays pinpoints novel candidate genes in Ewing sarcoma family of tumors , 2009, BMC Cancer.

[33]  A. Spurdle,et al.  Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results , 2008, Human mutation.

[34]  M. Goodman,et al.  Changes in Incidence and Survival of Ewing Sarcoma Patients Over the Past 3 Decades: Surveillance Epidemiology and End Results Data , 2008, Journal of pediatric hematology/oncology.

[35]  R. Malekzadeh,et al.  Germline BRCA2 mutations and the risk of esophageal squamous cell carcinoma , 2007, Oncogene.

[36]  S. Burchill,et al.  Chromosome 9p21 gene copy number and prognostic significance of p16 in ESFT , 2007, British Journal of Cancer.

[37]  J. Khan,et al.  Diagnosis of the small round blue cell tumors using multiplex polymerase chain reaction. , 2007, The Journal of molecular diagnostics : JMD.

[38]  T. Eisen,et al.  Variants in the GH-IGF axis confer susceptibility to lung cancer. , 2006, Genome research.

[39]  D. Hawkins,et al.  Survival after recurrence of Ewing's sarcoma family of tumors. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  F. Couch,et al.  Increased prevalence of the BRCA2 polymorphic stop codon K3326X among individuals with familial pancreatic cancer , 2005, Oncogene.

[41]  M. Ladanyi,et al.  Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  P. Sorensen,et al.  Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. , 2002, Cancer cell.

[43]  P. Sorensen,et al.  Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. , 2002, Cancer research.

[44]  A. Llombart‐Bosch,et al.  Molecular Analysis of the 9p21 Locus and p53 Genes in Ewing Family Tumors , 2001, Laboratory Investigation.

[45]  S. Chi,et al.  P53 mutations in Ewing's sarcoma. , 2001, Oncology reports.

[46]  G. Wei,et al.  Prognostic impact of INK4A deletion in Ewing sarcoma , 2000, Cancer.

[47]  Y. Kaneko,et al.  Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma. , 2000, Cancer genetics and cytogenetics.

[48]  Yusuke Nakamura,et al.  Identification of Rad51 alteration in patients with bilateral breast cancer , 2000, Journal of Human Genetics.

[49]  P. Ambros,et al.  Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors , 1999, Genes, chromosomes & cancer.

[50]  J. Fletcher,et al.  Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. , 1998, The American journal of pathology.

[51]  P. Sorensen,et al.  A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma , 1998, Nature Genetics.

[52]  H. Kovar,et al.  Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors , 1997, Oncogene.

[53]  O. Myklebost,et al.  Recurrent gains of 1q, 8 and 12 in the Ewing family of tumours by comparative genomic hybridization. , 1997, British Journal of Cancer.

[54]  Arndt Borkhardt,et al.  Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23) , 1997, Oncogene.

[55]  M. Stratton,et al.  A polymorphic stop codon in BRCA2 , 1996, Nature Genetics.

[56]  T. Triche,et al.  The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. , 1994, The New England journal of medicine.

[57]  G. Thomas,et al.  p53 mutations in human tumors with chimeric EWS/FLI/1 genes , 1994, International journal of cancer.

[58]  R. Hanada,et al.  Mutations of the p53 gene are involved in Ewing's sarcomas but not in neuroblastomas. , 1993, Cancer research.

[59]  H. Kovar,et al.  Narrow spectrum of infrequent p53 mutations and absence of MDM2 amplification in Ewing tumours. , 1993, Oncogene.

[60]  J. Thiery,et al.  Chromosomes in Ewing's sarcoma. I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12). , 1988, Cancer genetics and cytogenetics.