■尤因肉瘤是一种侵袭性间质恶性肿瘤,通常影响儿童和青少年。这种瘤形成的分子基础已得到充分报道,EWSR1/FLI1融合基因的形成是最常见的遗传发现。然而,该融合基因尚未被靶向治疗,也未被用作预后标志物。尚未确定其与导致尤因肉瘤发生的分子步骤的相关性。EWSR1/FLI1融合基因的产生,可归因于同时引入两个DNA双链断裂(DSB)。这项研究的范围是检测DNA修复缺陷与尤因肉瘤疾病的临床病理方面之间的任何关联。
■我们对35例诊断为尤文肉瘤的患者进行了表达分析,分析涉及非同源末端连接(NHEJ)和同源重组(HR)修复途径的基因。我们分析了参与NHEJ的6个基因的表达水平(XRCC4,XRCC5,XRCC6,POLλ,POLμ)和9个与HR有关的基因(RAD51,RAD52,RAD54,BRCA1,BRCA2,FANCC,FANCD,DNTM1,BRIT1)使用实时PCR。年龄,性别,原发肿瘤的位置,肿瘤大小,KI67有丝分裂计数,邻近组织的侵袭和治疗是统计学分析的临床病理参数。
■我们的结果表明,这两种DNA修复途径在尤因肉瘤中都失调。此外,xrcc4基因的低表达与更好的总体生存概率相关(p=0.032).
■我们的结果,即使是回顾性的,在少数患者中,强调DSBs修复的重要性,并提出此类肉瘤的潜在治疗靶点.
UNASSIGNED: Ewing sarcoma is an aggressive mesenchymal malignancy commonly affecting children and young adolescents. The molecular basis of this neoplasia is well reported with the formation of the EWSR1/FLI1 fusion gene being the most common genetic finding. However, this fusion gene has not been targeted therapeutically nor is being used as a prognostic marker. Its relevance regarding the molecular steps leading to Ewing sarcoma genesis are yet to be defined. The generation of the oncogenic EWSR1/FLI1 fusion gene, can be attributed to the simultaneous introduction of two DNA double-strand breaks (DSBs). The scope of this study is to detect any association between DNA repair deficiency and the clinicopathological aspects of Ewing\'s sarcoma disease.
UNASSIGNED: We have conducted an expression analysis of 35 patients diagnosed with Ewing sarcoma concerning the genes involved in non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways. We have analyzed the expression levels of 6 genes involved in NHEJ (XRCC4, XRCC5, XRCC6, POLλ, POLμ) and 9 genes involved in HR (RAD51, RAD52, RAD54, BRCA1, BRCA2, FANCC, FANCD, DNTM1, BRIT1) using real time PCR. Age, sex, location of primary tumor, tumor size, KI67, mitotic count, invasion of adjacent tissues and treatment were the clinicopathological parameters included in the statistical analysis.
UNASSIGNED: Our results show that both these DNA repair pathways are deregulated in Ewing sarcoma. In addition, low expression of the xrcc4 gene has been associated with better overall survival probability (p=0.032).
UNASSIGNED: Our results, even though retrospective and in a small number of patients, highlight the importance of DSBs repair and propose a potential therapeutic target for this type of sarcoma.