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.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065.
authors.forename: David
authors.initials: D
authors.lastname: Cobrinik
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: Maryam
authors.initials: M
authors.lastname: Hassimi
authors.forename: Satish K
authors.initials: SK
authors.lastname: Tickoo
authors.forename: Irene Y
authors.initials: IY
authors.lastname: Cheung
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000556:secondary; D002648:Child; D002675:Child, Preschool; D002877:Chromosomes, Human / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071447:N-Myc Proto-Oncogene Protein; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics* / Q000556:secondary; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C509186:TERT protein, human; D019098:Telomerase