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Telomere Trimming and DNA Damage as Signatures of High Risk Neuroblastoma.

TitleTelomere Trimming and DNA Damage as Signatures of High Risk Neuroblastoma.
Publication TypeJournal Article
Year of Publication2019
AuthorsYu EYoung, Cheung IY, Feng Y, Rabie MO, Roboz GJ, Guzman ML, Cheung N-KV, Lue NF
JournalNeoplasia
Volume21
Issue7
Pagination689-701
Date Published2019 07
ISSN1476-5586
KeywordsCell Proliferation, DNA Damage, Female, Genomic Instability, HeLa Cells, Humans, Male, Mutation, N-Myc Proto-Oncogene Protein, Neuroblastoma, Telomerase, Telomere, Telomere Homeostasis, X-linked Nuclear Protein
Abstract

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.

DOI10.1016/j.neo.2019.04.002
Alternate JournalNeoplasia
PubMed ID31128432
PubMed Central IDPMC6535646
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States

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