Molecular Mechanism of Telomere Length Dynamics and Its Prognostic Value in Pediatric Cancers

Abstract

Background: We aimed to systematically evaluate telomere dynamics across a spectrum of pediatric cancers, search for underlying molecular mechanisms, and assess potential prognostic value.

Methods: 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.

Results: 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).

Conclusion: 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.

Figure 1.

Boxplot of log₂ of tumor and normal (T/N) ratio of telomere fractions across pediatric cancer subtypes. Boxes colored in red, blue, and green are for brain tumors, hematological cancers, and solid tumors, respectively. Samples with log₂ of T/N ratio of telomere fractions greater than 0 (above the dotted line) had telomere lengthening, otherwise, telomere shortening. ACT = adrenocortical tumor; AMLM7 = M7 acute myeloid leukemia; BALL = B-lineage acute lymphoblastic leukemia; CBF = core binding factor acute myeloid leukemia; CPC = choroid plexus carcinoma; E2A = E2A-PBX1 acute lymphoblastic lymphoma; EPD = ependymoma; ERG = ERG acute lymphoblastic leukemia; ETV = ETV6-RUNX1 acute lymphoblastic leukemia; EWS = Ewing sarcoma; HGG = high-grade glioma; HYPO = hypodiploid acute lymphoblastic leukemia; INF = infant acute lymphoblastic leukemia; LGG = low-grade glioma; MB = medulloblastoma; MEL = melanoma; NBL = neuroblastoma; OS = osteosarcoma; PHALL = Philadelphia acute lymphoblastic leukemia; RB = retinoblastoma; RHB = rhabdomyosarcoma; TALL = T-lineage acute lymphoblastic leukemia; HYPER = hyperdiploid acute lymphoblastic leukemia.

Figure 2.

Molecular mechanisms for telomere lengthening in tumors. Number of samples with telomere lengthening had ATRX, TERT, or both or unknown mechanisms plotted for each subtype. Subtypes with fewer than five samples were pooled into one of the “other” groups. Note, one NBL patient (SJNBL044) had both ATRX alteration and TERT-expressing (depicted as a blue-colored bar). ACT = adrenocortical tumor; E2A = acute lymphoblastic leukemia B-lineage E2A-PBX1 subtype; HGG = high-grade glioma; NBL = neuroblastoma; OS = osteosarcoma.

Figure 3.

Distribution of TERT expression and ATRX expression in groups with excessive telomere lengthening, moderate change of telomeres, and excessive telomere shortening. A) TERT in brain tumors; B) TERT in hematological cancers; C) TERT in solid tumors; D) ATRX in brain tumors; E) ATRX in hematological cancers; and F) ATRX in solid tumors.

Figure 4.

Coexpression of PAX5 and TERT in E2A ALL (E2A), infant ALL (INF), and other subtypes of hematological cancers. Expression of TERT measured in FPKM (brown-colored bar and Y-axis on the left); expression of PAX5 measured in FPKM (blue-colored bar and Y-axis on the right).