Telomeres play important roles in genome stability and cell proliferation. High risk neuroblastoma (HRNB), an aggressive childhood cancer, is especially reliant on telomere maintenance. Three recurrent genetic aberrations in HRNB (MYCN amplification, TERT re-arrangements, and ATRX mutations) are mutually exclusive and each capable of promoting telomere maintenance mechanisms (i.e., through telomerase or ALT). We analyzed a panel of 5 representative HRNB cell lines and 30 HRNB surgical samples using assays that assess average telomere lengths, length distribution patterns, single-stranded DNA on the G- and C-strand, as well as extra-chromosomal circular telomeres. Our analysis pointed to substantial and variable degrees of telomere DNA damage in HRNB, including pervasive oxidative lesions. Moreover, unlike other cancers, neuroblastoma consistently harbored high levels of C-strand ssDNA overhangs and t-circles, which are consistent with active "telomere trimming". This feature is observed in both telomerase- and ALT-positive tumors and irrespective of telomere length distribution. Moreover, evidence for telomere trimming was detected in normal neural tissues, raising the possibility that TMMs in HRNB evolved in the face of a canonical developmental program of telomere shortening. Telomere trimming by itself appears to distinguish neuroectodermal derived tumors from other human cancers, a distinguishing characteristic with both biologic and therapeutic implications.

中文翻译：

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端粒修饰和DNA损伤是高危神经母细胞瘤的特征。

端粒在基因组稳定性和细胞增殖中起重要作用。高危神经母细胞瘤（HRNB）是一种侵略性的儿童期癌症，尤其依赖于端粒的维持。HRNB中的三个重复遗传畸变（MYCN扩增，TERT重排和ATRX突变）是互斥的，并且每个都能促进端粒维持机制（即通过端粒酶或ALT）。我们使用评估平均端粒长度，长度分布模式，G链和C链上的单链DNA以及染色体外环状端粒的分析方法，分析了5组代表性HRNB细胞系和30份HRNB外科手术样品。我们的分析指出了HRNB中端粒DNA损伤的程度不同，包括广泛的氧化损伤。而且，与其他癌症不同，神经母细胞瘤始终具有高水平的C链ssDNA突出端和T环，这与活跃的“端粒修整”相一致。在端粒酶和ALT阳性肿瘤中均观察到此特征，而与端粒长度分布无关。此外，在正常的神经组织中检测到端粒修整的证据，这增加了HRNB中TMM面对端粒缩短的规范发展程序而进化的可能性。端粒修饰本身似乎可以将神经外胚层来源的肿瘤与其他人类癌症区分开，这是具有生物学和治疗意义的显着特征。在端粒酶和ALT阳性肿瘤中均观察到此特征，而与端粒长度分布无关。此外，在正常的神经组织中检测到端粒修整的证据，这增加了HRNB中TMM面对端粒缩短的规范发展程序而进化的可能性。端粒修饰本身似乎可以将神经外胚层来源的肿瘤与其他人类癌症区分开，这是具有生物学和治疗意义的显着特征。在端粒酶和ALT阳性肿瘤中均观察到此特征，而与端粒长度分布无关。此外，在正常的神经组织中检测到端粒修整的证据，这增加了HRNB中TMM面对端粒缩短的规范发展程序而进化的可能性。端粒修饰本身似乎可以将神经外胚层来源的肿瘤与其他人类癌症区分开，这是具有生物学和治疗意义的显着特征。