1. ¹Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany
2. ²Department of Pediatric Oncology and Hematology, University Hospital of Essen, Germany
3. ³Department of Theoretical Bioinformatics (B080), German Cancer Research Center, Heidelberg, Germany
4. ⁴Department of Tumour Genetics (B030), German Cancer Research Center, Heidelberg, Germany

Correspondence: Dr M Fischer, Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Kerpener Street 62, Cologne 50924, Germany. E-mail: matthias.fischer@uk-koeln.de

Received 6 September 2007; Revised 24 October 2007; Accepted 21 November 2007; Published online 17 December 2007.

Abstract

Cell adhesion molecule 1 (CADM1) is a putative tumour suppressor gene, which is downregulated in many solid tumours. In neuroblastoma, loss of CADM1 expression has recently been found in disseminated tumours with adverse outcome, prompting us to investigate its role in neuroblastoma tumour progression. Oligonucleotide-microarray analysis of 251 neuroblastoma specimens demonstrated that CADM1 downregulation is associated with unfavourable prognostic markers like disseminated stage 4, age >18 months, MYCN amplification and chromosome 11q alterations (P<0.001 each). Furthermore, low CADM1 expression was significantly correlated with unfavourable gene expression-based classification (P<0.001) and adverse patient outcome (P<0.001). Bisulphite sequencing and genetic analysis of 18 primary neuroblastomas suggested that neither haploinsufficiency nor hypermethylation is regularly involved in CADM1 gene silencing in neuroblastoma, which is in contrast to results obtained in other malignancies. In addition, no mutations disrupting the CADM1 reading frame were found in 25 primary neuroblastomas. Over-expression of CADM1 in neuroblastoma cells resulted in significant reduction of proliferation, viability and colony formation in soft agar. Collectively, our results suggest that downregulation of CADM1 tumour suppressor gene expression is a critical event in neuroblastoma pathogenesis resulting in tumour progression and unfavourable patient outcome.