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Alternative lengthening of telomeres—An enhanced chromosomal instability in aggressive non‐ MYCN amplified and telomere elongated neuroblastomas
Author(s) -
Lundberg Gisela,
Sehic Daniel,
Länsberg JohnKalle,
Øra Ingrid,
Frigyesi Attila,
Castel Victoria,
Navarro Samuel,
Piqueras Marta,
Martinsson Tommy,
Noguera Rosa,
Gisselsson David
Publication year - 2011
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20850
Subject(s) - telomere , chromosome instability , genome instability , biology , neuroblastoma , cancer research , anaphase , microbiology and biotechnology , cell , cell culture , genetics , cell cycle , dna , gene , dna damage , chromosome
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. © 2011 Wiley‐Liss, Inc.