Expression of the tumour suppressor gene CADM1 is associated with favourable outcome and inhibits cell survival in neuroblastoma.
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.
Nowacki
S
S
Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany.
Skowron
M
M
Oberthuer
A
A
Fagin
A
A
Voth
H
H
Brors
B
B
Westermann
F
F
Eggert
A
A
Hero
B
B
Berthold
F
F
Fischer
M
M
D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics* / Q000502:physiology; D007223:Infant; D007231:Infant, Newborn; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation / Q000502:physiology; D009447:Neuroblastoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
D014408:Biomarkers, Tumor; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D008565:Membrane Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins