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

Autor:	Wang Z; Department of Epidemiology and Cancer Control.; Department of Computational Biology., Rice SV; Department of Computational Biology., Chang TC; Department of Computational Biology., Liu Y; Department of Computational Biology., Liu Q; School of Public Health, University of Alberta, Edmonton, Alberta, Canada., Qin N; Department of Epidemiology and Cancer Control., Putnam DK; Department of Computational Biology., Shelton K; Department of Epidemiology and Cancer Control., Lanctot JQ; Department of Epidemiology and Cancer Control., Wilson CL; Department of Epidemiology and Cancer Control., Ness KK; Department of Epidemiology and Cancer Control.; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Rusch MC; Department of Computational Biology., Edmonson MN; Department of Computational Biology., Wu G; Department of Computational Biology., Easton J; Department of Computational Biology., Kesserwan CA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Downing JR; Department of Pathology., Chen X; Department of Computational Biology., Nichols KE, Yasui Y; Department of Epidemiology and Cancer Control., Robison LL; Department of Epidemiology and Cancer Control., Zhang J; Department of Computational Biology.
Jazyk:	angličtina
Zdroj:	Journal of the National Cancer Institute [J Natl Cancer Inst] 2020 Jul 01; Vol. 112 (7), pp. 756-764.
DOI:	10.1093/jnci/djz210
Abstrakt:	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. (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu