Abstract
Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma.
Highlights
Neuroblastoma (NB) is the most frequent solid tumor of infancy
In a second series of NB consisting of 110 specimens for which both ATM expression and ATM locus status were available, 11q deletion at the ATM locus correlates with lower event-free survival (EFS) and overall survival (OS) (Figure 2, left), and this is independent of MYCN (Supplementary Figure S2)
Several studies reported an association between 11q aberrations and unfavorable outcome [2, 36,37,38,39] suggesting that patients presenting with localized and 4S stages NB and 11q deletion would benefit from a more intensive therapy
Summary
Neuroblastoma (NB) is the most frequent solid tumor of infancy. It originates from the sympathetic nervous system (most frequently in adrenal glands), accounts for 8–10% of malignancies in childhood, and causes 15% of cancer-related deaths in children. Unbalanced gain or loss or chromosomal regions (in particular, the loss of chromosome 1p or 11q, the gain of 17q, or the amplification of the MYCN oncogene) have been associated with an adverse prognosis. Poor prognosis NB is subdivided into two main groups: NB www.impactjournals.com/oncotarget with amplification of the MYCN oncogene (20% of cases) and NB with unbalanced loss of chromosome 11q (30–40% of cases). MYCN amplification and 11q loss occur together in NB very rarely (1.7% of cases, as opposed to an expected frequency of 8% if these two events occurred independently) suggesting that these two cytogenetic anomalies might be incompatible, for reasons that are currently unknown [1, 2]
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