Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Nat Commun. 2021 Feb 24;12(1):1269. doi: 10.1038/s41467-021-21247-8.
Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.
端粒酶激活或端粒的替代性延长（ALT）维持端粒是神经母细胞瘤预后不良的主要决定因素。在这里，我们对原发性和复发性神经母细胞瘤（n=760）进行了 ALT 筛选，并通过多组学分析对其特征进行了描述。与其他神经母细胞瘤亚型相比，ALT 阳性肿瘤在基于人群的复发性病例临床测序研究队列中具有明显的分子特征。它们显示出 ATRX/DAXX 复合物丰度降低，这是由于 ATRX 突变（55%）或低蛋白表达所致。ATRX 识别的异染色质组蛋白标记 H3K9me3 在 ALT 阳性肿瘤的端粒处富集。值得注意的是，我们发现了高频的端粒重复序列，这些序列在 chr1q42.2 上具有神经母细胞瘤 ALT 特异性热点，并且相邻的染色体片段丢失形成新的端粒。ALT 阳性神经母细胞瘤的增殖速度较慢，这反映在疾病的临床病程延长上。然而，具有 ALT 阳性神经母细胞瘤的儿童预后不良。
