title: Alternative lengthening of telomeres--an enhanced chromosomal instability in aggressive non-MYCN amplified and telomere elongated neuroblastomas.
abstract: Telomere length alterations are known to cause genomic instability and influence clinical course in several tumor types, but have been little investigated in neuroblastoma (NB), one of the most common childhood tumors. In the present study, telomere-dependent chromosomal instability and telomere length were determined in six NB cell lines and fifty tumor biopsies. The alternative lengthening of telomeres (ALT) pathway was assayed by scoring ALT-associated promyelocytic leukemia (PML) bodies (APBs). We found a reduced probability of overall survival for tumors with increased telomere length compared to cases with reduced or unchanged telomere length. In non-MYCN amplified tumors, a reduced or unchanged telomere length was associated with 100% overall survival. Tumor cells with increased telomere length had an elevated frequency of APBs, consistent with activation of the ALT pathway. The vast majority of tumor biopsies and cell lines exhibited an elevated rate of anaphase bridges, suggesting telomere-dependent chromosomal instability. This was more pronounced in tumors with increased telomere length. In cell lines, there was a close correlation between lack of telomere-protective TTAGGG-repeats, anaphase bridging, and remodeling of oncogene sequences. Thus, telomere-dependent chromosomal instability is highly prevalent in NB, and may contribute to the complexity of genomic alterations as well as therapy resistance in the absence of MYCN amplification and in this tumor type.
authors.affiliation: Department of Clinical Genetics, Lund University, University and Regional Laboratories, Skåne University Hospital, Lund, Sweden. gisela.lundberg@med.lu.se
authors.forename: Gisela
authors.initials: G
authors.lastname: Lundberg
authors.forename: Daniel
authors.initials: D
authors.lastname: Sehic
authors.forename: John-Kalle
authors.initials: JK
authors.lastname: Länsberg
authors.forename: Ingrid
authors.initials: I
authors.lastname: Øra
authors.forename: Attila
authors.initials: A
authors.lastname: Frigyesi
authors.forename: Victoria
authors.initials: V
authors.lastname: Castel
authors.forename: Samuel
authors.initials: S
authors.lastname: Navarro
authors.forename: Marta
authors.initials: M
authors.lastname: Piqueras
authors.forename: Tommy
authors.initials: T
authors.lastname: Martinsson
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
mesh_terms: D000328:Adult; D000705:Anaphase; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D043171:Chromosomal Instability; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D055815:Young Adult
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D019098:Telomerase