Studies of the genomic stability of Ewing sarcoma (EwS) have produced contradictory findings. While they are generally characterized by low mutation rates of individual genes, several cases exhibit genomic alterations that manifest as chromosomal gains and losses. Taken together, these alterations represent independent biomarkers for EwS, such as loss of heterozygosity (LOH) or an altered genome. Patients with primary EwS tumors with fewer than three copy number alterations (CNAs) have a better prognosis than those with more CNAs. The functional mechanisms underlying this chromosomal instability are not yet clear. However, there are indications that this may be directly caused by theEWSR1::ETStranslocations that are characteristic of EwS. The transcriptional behavior of the chimeric transcription factor EWSR1-FLI1 leads to the formation of R-loop DNA–RNA hybrids that form when RNA binds back to DNA during transcription and increased replication stress, which may result in structural chromosomal changes. Additionally, the formation of EWSR1 fusion genes in EwS results in the loss of one or both wild-type EWSR1 alleles in sarcoma cells. As chromosome segregation has been observed under loss of wild-type EWSR1, EWSR1 loss has been proposed as a potential source of LOH. So, it is highly probable that a chromosomal translocation and the subsequent formation of the EWSR1-ETS fusion protein cause the genomic alterations in EwS. This indicates that targeted therapy should be directed against the CNA and LOH biology caused by the fusion protein.
关于尤文肉瘤（EwS）基因组稳定性的研究呈现出相互矛盾的发现。尽管这类肿瘤通常表现为单个基因的低突变率，但部分病例确实存在表现为染色体增加或缺失的基因组改变。总体而言，这些改变构成了尤文肉瘤的独立生物标志物，例如杂合性缺失（LOH）或基因组变异。原发性尤文肉瘤患者中，拷贝数变异（CNAs）少于三处的患者比具有更多CNAs的患者预后更好。这种染色体不稳定的功能机制尚不明确，但有迹象表明这可能直接由尤文肉瘤特征性的EWSR1::ETS易位所引起。嵌合转录因子EWSR1-FLI1的转录行为会导致R-loop DNA-RNA杂交体的形成——这种结构产生于转录过程中RNA回折与DNA结合的过程，同时会增强复制压力，从而可能引发染色体结构改变。此外，尤文肉瘤中EWSR1融合基因的形成会导致肉瘤细胞中一个或两个野生型EWSR1等位基因的缺失。由于在野生型EWSR1缺失条件下观察到染色体分离异常，EWSR1缺失被认为是LOH的潜在来源。因此，染色体易位及随后形成的EWSR1-ETS融合蛋白极有可能是导致尤文肉瘤基因组改变的根源。这表明靶向治疗应针对由融合蛋白引起的CNA和LOH生物学机制展开。
肿瘤(癌症)患者之家