Recurrent pre-existing and acquired DNA copy number alterations, including focal TERT gains, in neuroblastoma central nervous system metastases Journal Article


Authors: Cobrinik, D.; Ostrovnaya, I.; Hassimi, M.; Tickoo, S. K.; Cheung, I. Y.; Cheung, N. K. V.
Article Title: Recurrent pre-existing and acquired DNA copy number alterations, including focal TERT gains, in neuroblastoma central nervous system metastases
Abstract: Stage 4 neuroblastomas have a high rate of local and metastatic relapse and associated disease mortality. The central nervous system (CNS) is currently one of the most common isolated relapse sites, yet the genomic alterations that contribute to these metastases are unknown. This study sought to identify recurrent DNA copy number alterations (CNAs) and target genes relating to neuroblastoma CNS metastases by studying 19 pre-CNS primary tumors and 27 CNS metastases, including 12 matched pairs. SNP microarray analyses revealed that MYCN amplified (MYCNA) tumors had recurrent CNAs different from non-MYCNA cohorts. Several CNAs known to be prevalent among primary neuroblastomas occurred more frequently in CNS metastases, including 4p-, 7q+, 12q+, and 19q- in non-MYCNA metastases, and 9p- and 14q- irrespective of MYCNA status. In addition, novel CNS metastases-related CNAs included 18q22.1 gains in non-MYCNA pre-CNS primaries and 5p15.33 gains and 15q26.1→tel losses in non-MYCNA CNS metastases. Based on minimal common regions, gene expression, and biological properties, TERT (5p), NR2F2 (15q), ALDH1A3 (15q), CDKN2A (9p), and possibly CDH7 and CDH19 (18q) were candidate genes associated with the CNS metastatic process. Notably, the 5p15 minimal common region contained only TERT, and non-MYCNA CNS metastases with focal 5p15 gains had increased TERT expression, similar to MYCNA tumors. These findings suggest that a specific genomic lesion (18q22.1 gain) predisposes to CNS metastases and that distinct lesions are recurrently acquired during metastatic progression. Among the acquired lesions, increased TERT copy number and expression appears likely to function in lieu of MYCNA to promote CNS metastasis. © 2013 Wiley Periodicals, Inc.
Keywords: child; human tissue; school child; primary tumor; unclassified drug; single nucleotide polymorphism; cancer susceptibility; gene expression; protein; chromosome 9p; gene frequency; infant; neuroblastoma; microarray analysis; telomerase reverse transcriptase; metastasis potential; cyclin dependent kinase inhibitor 2a; genetic risk; genetic predisposition; chromosome 12q; chromosome 14q; chromosome 5p; chromosome 7q; chromosome 15q; central nervous system metastasis; copy number variation; chromosome 18q; chromosome 19q; aldh1a3 protein; cdh19 protein; cdh7 protein; nr2f2 protein; chromosome 4p; dna copy number alteration
Journal Title: Genes Chromosomes and Cancer
Volume: 52
Issue: 12
ISSN: 1045-2257
Publisher: Wiley Periodicals, Inc  
Date Published: 2013-10-10
Start Page: 1150
End Page: 1166
Language: English
DOI: 10.1002/gcc.22110
PROVIDER: scopus
PUBMED: 24123354
DOI/URL:
Notes: --- - "Export Date: 2 December 2013" - "CODEN: GCCAE" - "Source: Scopus"
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MSK Authors
  1. Nai-Kong Cheung
    447 Cheung
  2. Satish K Tickoo
    370 Tickoo
  3. Irene Y Cheung
    75 Cheung