Department of Epidemiology and Cancer Control.
Department of Computational Biology.
J Natl Cancer Inst. 2020 Jul 1;112(7):756-764. doi: 10.1093/jnci/djz210.
We aimed to systematically evaluate telomere dynamics across a spectrum of pediatric cancers, search for underlying molecular mechanisms, and assess potential prognostic value.
The fraction of telomeric reads was determined from whole-genome sequencing data for paired tumor and normal samples from 653 patients with 23 cancer types from the Pediatric Cancer Genome Project. Telomere dynamics were characterized as the ratio of telomere fractions between tumor and normal samples. Somatic mutations were gathered, RNA sequencing data for 330 patients were analyzed for gene expression, and Cox regression was used to assess the telomere dynamics on patient survival.
Telomere lengthening was observed in 28.7% of solid tumors, 10.5% of brain tumors, and 4.3% of hematological cancers. Among 81 samples with telomere lengthening, 26 had somatic mutations in alpha thalassemia/mental retardation syndrome X-linked gene, corroborated by a low level of the gene expression in the subset of tumors with RNA sequencing. Telomerase reverse transcriptase gene amplification and/or activation was observed in 10 tumors with telomere lengthening, including two leukemias of the E2A-PBX1 subtype. Among hematological cancers, pathway analysis for genes with expressions most negatively correlated with telomere fractions suggests the implication of a gene ontology process of antigen presentation by Major histocompatibility complex class II. A higher ratio of telomere fractions was statistically significantly associated with poorer survival for patients with brain tumors (hazard ratio = 2.18, 95% confidence interval = 1.37 to 3.46).
Because telomerase inhibitors are currently being explored as potential agents to treat pediatric cancer, these data are valuable because they identify a subpopulation of patients with reactivation of telomerase who are most likely to benefit from this novel therapeutic option.
我们旨在系统地评估儿科癌症谱中端粒动力学，寻找潜在的分子机制，并评估其潜在的预后价值。
从儿科癌症基因组计划中 23 种癌症类型的 653 名患者的配对肿瘤和正常样本的全基因组测序数据中确定端粒读取的分数。端粒动力学的特征是肿瘤和正常样本之间端粒分数的比值。收集体细胞突变，分析 330 名患者的 RNA 测序数据以进行基因表达，并使用 Cox 回归评估端粒动力学对患者生存的影响。
在 28.7%的实体瘤、10.5%的脑肿瘤和 4.3%的血液恶性肿瘤中观察到端粒延长。在 81 个端粒延长的样本中，26 个样本中存在α地中海贫血/智力迟钝综合征 X 连锁基因的体细胞突变，通过 RNA 测序的肿瘤亚组中该基因表达水平较低得到证实。在 10 个端粒延长的肿瘤中观察到端粒酶逆转录酶基因扩增和/或激活，包括两种 E2A-PBX1 亚型的白血病。在血液恶性肿瘤中，与端粒分数最负相关的基因的通路分析表明，主要组织相容性复合物 II 类抗原呈递的基因本体过程的含义。较高的端粒分数比与脑肿瘤患者的生存较差具有统计学显著相关性（危险比=2.18，95%置信区间=1.37 至 3.46）。
由于端粒酶抑制剂目前正在被探索作为治疗儿科癌症的潜在药物，这些数据很有价值，因为它们确定了一个端粒酶重新激活的患者亚群，他们最有可能从这种新的治疗选择中受益。
