Brohl Andrew S, Solomon David A, Chang Wendy, Wang Jianjun, Song Young, Sindiri Sivasish, Patidar Rajesh, Hurd Laura, Chen Li, Shern Jack F, Liao Hongling, Wen Xinyu, Gerard Julia, Kim Jung-Sik, Lopez Guerrero Jose Antonio, Machado Isidro, Wai Daniel H, Picci Piero, Triche Timothy, Horvai Andrew E, Miettinen Markku, Wei Jun S, Catchpool Daniel, Llombart-Bosch Antonio, Waldman Todd, Khan Javed
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.
Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.
PLoS Genet. 2014 Jul 10;10(7):e1004475. doi: 10.1371/journal.pgen.1004475. eCollection 2014 Jul.
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.
尤因肉瘤家族性肿瘤（EFT）是一组发生于儿童和青年的高度恶性小圆蓝细胞瘤。我们在此报告了迄今为止对101例EFT（65个肿瘤和36个细胞系）进行的最大规模基因组调查。通过结合全基因组测序和靶向测序方法，我们发现EFT的突变负荷非常低（0.15个突变/Mb），但黏连蛋白复合体亚基STAG2存在频繁的有害突变（21.5%的肿瘤、44.4%的细胞系），CDKN2A纯合缺失（分别为13.8%和50%）以及TP53突变（分别为6.2%和71.9%）。我们还注意到，与人群数据相比，EFT患者样本中BRCA2 K3326X多态性的患病率有所增加（7.3%，比值比7.1，p = 0.006）。通过全转录组测序，我们发现11%病理诊断为EFT的肿瘤缺乏典型的EWSR1融合致癌基因，且这些肿瘤没有特征性的尤因肉瘤基因表达特征。我们鉴定出了含有新型融合基因的样本，包括FUS-NCATc2和CIC-FOXO4，它们可能代表不同的小圆蓝细胞瘤变体。在一个独立的EFT组织微阵列队列中，我们表明免疫组化检测到的STAG2缺失可能与疾病进展更严重有关（p = 0.15），总体生存率略有下降（p = 0.10）。这些结果显著推进了我们对尤因肉瘤基因组和分子基础的理解，并为进一步改善诊断、预后和精准治疗测试奠定了基础。
