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: Andrew S Brohl, David A Solomon, Wendy Chang, Jianjun Wang, Young Song, Sivasish Sindiri, Rajesh Patidar, Laura Hurd, Li Chen, Jack F Shern, Hongling Liao, Xinyu Wen, Julia Gerard, Jung-Sik Kim, Jose Antonio Lopez Guerrero, Isidro Machado, Daniel H Wai, Piero Picci, Timothy Triche, Andrew E Horvai, Markku Miettinen, Jun S Wei, Daniel Catchpool, Antonio Llombart-Bosch, Todd Waldman, Javed Khan
• Journal: PLoS genetics (PLoS Genet) Vol. 10 Issue 7 Pg. e1004475 (Jul 2014) ISSN: 1553-7404 [Electronic] United States
• PMID: 25010205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Nuclear
• Cell Cycle Proteins
• Neoplasm Proteins
• STAG2 protein, human

Topics

• Adolescent
• Adult
• Antigens, Nuclear (genetics)
• Cell Cycle Proteins
• Cell Line, Tumor
• Child
• Child, Preschool
• Disease-Free Survival
• Female
• Gene Deletion
• Genome, Human
• High-Throughput Nucleotide Sequencing
• Humans
• Infant
• Male
• Mutation (genetics)
• Neoplasm Proteins (genetics)
• Sarcoma, Ewing (etiology, genetics, pathology)