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Ref ID: 029.1
EMP3, A Putative Tumor Suppressor Gene Mapping At 19q13.3, Is Epigenetically
Silenced In Neuroblastoma By Promoter Hypermethylation and May Have
Prognostic Value
Miguel Alaminos1, Veronica Davalos1, Nai-Kong V Cheung2, William L Gerald2, Manel Esteller1
Cancer Epigenetics Laboratory1, Spanish National Cancer Center (CNIO), Madrid, Spain; Memorial Sloan-Kettering Centre2, New
York, USA.
BACKGROUND: Inactivation of tumor suppressor genes may occur by epigenetic silencing associated
with the hypermethylation of the CpG islands at the promoter regions of these genes. A putative
neuroblastoma suppressor gene located at 19q13.3 has not been identified to date by using standard
genetic and molecular biology approaches.
METHODS: We analyzed 89 neuroblastoma tumors, 10 ganglioneuromas and 9 normal bone-marrow
samples by Affymetrix Human U95v2 oligonucleotide arrays (62839 probe-sets). Candidate genes were
analyzed by methylation-specific-PCR (MSP) in 116 human neuroblastic tumors, 10 neuroblastoma cell
lines, 41 gliomas and 47 non-neuroblastoma cell lines.
RESULTS: 100 genes were significantly downregulated by expression array in neuroblastoma tumors
when compared with ganglioneuromas and normal bone marrows, including a gene located at 19q13.3
(EMP3, epithelial membrane protein 3, involved in cell proliferation and cell-cell interactions). By MSP,
EMP3 promoter was hypermethylated (24.1% neuroblastic tumors, 55.5% neuroblastoma cell lines, 39%
gliomas and 40.4% non-neuroblastoma lines). Demethylating agent 5-aza-2-deoxycytidine restored
EMP3 gene expression. EMP3 promoter hypermethylation was associated with poor survival (KaplanMeier p=0.03), with strong correlation with death (p=0.03; r=0.19). For both local-regional and metastatic
neuroblastoma, death rate was higher with methylated EMP3 (33.3% for LR and 78.6% for stage 4) than
with unmethylated EMP3 (13.3% for LR and 46.1% for stage 4).
CONCLUSIONS: Epigenetic silencing of the gene EMP3 by promoter hypermethylation is associated with
a poor survival for both local-regional and stage 4 neuroblastomas. This gene could be a tumor
suppressor gene located at 19q13.3.
Presentation mode(s): ORAL-PRESENTATION – PC-PROJECTOR
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